RARE DISEASE
Krabbe disease
Krabbe disease
Krabbe disease
Synonyms: GALC deficiency, Galactocerebrosidase deficiency, Galactosylceramidase deficiency, Globoid cell leukodystrophy
Synonyms: GALC deficiency, Galactocerebrosidase deficiency, Galactosylceramidase deficiency, Globoid cell leukodystrophy
Synonyms: GALC deficiency, Galactocerebrosidase deficiency, Galactosylceramidase deficiency, Globoid cell leukodystrophy
Drug discovery
11
drugs
With orphan designations
Overview
Krabbe disease is a rare autosomal recessive lysosomal disorder caused by GALC gene mutations, leading to galactocerebrosidase deficiency and toxic psychosine accumulation. This results in progressive demyelination of the CNS and PNS. Infantile-onset (85-90% of cases) manifests as irritability, spasticity, and developmental regression before age 6 months, with death typically by age 2–3 years. Late-onset forms present with gait disturbances, neuropathy, and vision loss, progressing to death within 10 years of diagnosis [1][5][6][9][14].
Burden
Clinical: 90% of infantile patients die by age 2; late-onset forms cause cumulative disability (blindness, paralysis) [1][6][10][14].
Economic: $51.5M annual hospitalization charges for 98 US patients (2016 data); 260 inpatient admissions/3-year period [2].
Psychosocial: High caregiver burden due to rapid neurological decline; stem cell transplant mortality reaches 15–20% [3][10][13].
Therapies
HSCT/Cord blood transplant: Only disease-modifying option; most effective if performed pre-symptomatically (≤30 days old). Stabilizes cognition but does not reverse existing damage [3][7][11][19].
Supportive care: Anticonvulsants, muscle relaxants, and enteral feeding support [9][13][15].
Experimental therapies: Intrathecal AAV9 gene therapy restores GALC activity in preclinical models, extending survival 7-fold in animal studies [11][19].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
459 drug discovery papers about Krabbe disease, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
459 drug discovery papers about Krabbe disease, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-08-13 | Survival benefit and immune-related toxicities after hematopoietic stem cell transplantation in Krabbe disease: a systematic review and meta-analysis
Background Krabbe disease is a rare, rapidly progressive leukodystrophy with high early mortality. Hematopoietic stem cell transplantation (HSCT) is the main disease-modifying intervention used in clinical practice and may act through donor-derived myeloid and immune-cell replacement, enzymatic cross-correction, and immunomodulation. However, its benefits and immune-related toxicities remain incompletely quantified. Methods We conducted a systematic review and meta-analysis of studies reporting HSCT outcomes in genetically or enzymatically confirmed Krabbe disease. The primary outcome was overall survival (OS). Secondary outcomes included 5-year OS, transplant-related mortality (TRM), acute and chronic graft-versus-host disease (aGVHD and cGVHD), neurological stability, and MRI stability. For OS, publication bias or small-study effects were assessed using funnel-plot inspection and Egger’s regression test. Exploratory univariable meta-regression examined total study sample size, publication year, and Newcastle–Ottawa Scale (NOS) score, and robustness was assessed using leave-one-out sensitivity analysis. Results Fifteen studies involving 141 patients were included. Pooled OS after HSCT was 84% (95% CI, 75%–93%), 5-year OS was 80% (69%–92%), and TRM was 7% (1%–13%). The pooled incidences of aGVHD and cGVHD were 53% (16%–90%) and 25% (0%–53%), respectively. Neurological stability was reported in only four studies including 15 patients (77%; 31%–100%), and MRI stability in four studies including 32 patients (49%; 7%–90%); both estimates showed substantial heterogeneity and wide confidence intervals. Subgroup analyses by disease-onset age, pre-transplant symptom status, and age at HSCT showed no statistically significant OS differences. Egger’s test detected no significant funnel-plot asymmetry (P = 0.569). Leave-one-out estimates ranged from 82% to 86%. Meta-regression showed inverse associations of reported OS with total study sample size and NOS score (both P < 0.001), whereas publication year was not significant (P = 0.118). Conclusion HSCT is associated with favorable survival and relatively low pooled TRM in selected patients with Krabbe disease. However, survival should not be interpreted as preservation of neurological function, because neurological, MRI, and GVHD outcomes were reported in few studies and patients and remained heterogeneous and imprecisely estimated. These findings require cautious interpretation but provide clinically useful benchmark data for counseling and comparison with emerging cellular and gene-based therapies. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261285624.
2026-04-23 | Stem cell therapy for rare neurological diseases: translational research opportunities
Stem cell therapy is being explored for several rare neurological conditions in humans given their potential immunomodulatory, reparative, and regenerative capabilities. Existing standard treatments for most neuroinflammatory and neurodegenerative disorders are primarily palliative, focusing on symptom management rather than addressing underlying disease pathology. The genetic and pathophysiological parallels between many human and animal neurological diseases suggest that companion animals may serve as valuable translational models to drive stem cell research forward. Several rare human neurological conditions with companion animal (particularly canine) correlates include fulminant multiple sclerosis (MS), myasthenia gravis, amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Dravet and Lennox-Gastaut Syndromes, Globoid Cell Leukodystrophy/Krabbe Disease, viral encephalitis, and glioblastoma multiforme (GBM). Validating the safety and feasibility of stem cell transplantation in companion animal models has enabled the development and expansion of innovative therapies. Stem cell therapy may hold promise as a novel treatment option for some rare and aggressive human and companion animal neurological diseases with limited treatment options.
2026-01-28 | Long-term neurological outcome after hematopoietic stem cell transplant in juvenile Krabbe disease.
Globoid cell leukodystrophy (GLD) is a progressive neurodegenerative disease caused by galactocerebrosidase deficiency. Juvenile phenotypes-onset between ages 3 and 16-account for up to 25% of cases. Hematopoietic stem cell transplantation (HSCT) is the only available treatment, yet only eight juvenile-onset cases treated with HSCT have been reported, with heterogeneously collected data. We aim to comprehensively evaluate long-term neurological outcomes post-HSCT in juvenile GLD. We conducted a retrospective study of all juvenile GLD patients treated with HSCT and followed at our Institution. We assessed survival, neurological status, disability (modified Rankin Scale), cognitive outcomes, GALC activity, serial MRIs (Loes score), evoked potentials (internal scoring system), and nerve conduction studies at pre-HSCT, first post-HSCT visit, and last follow-up. Six biochemically and genetically confirmed juvenile GLD cases were included. Four were symptomatic at diagnosis; two were pre-symptomatic. All survived to last follow-up (range 9 years, 2 months-19 years, and 8 months). Four achieved near-normal cognitive, motor, and functional status. Two symptomatic patients-with extensive pre-HSCT white matter disease and specific pre-HSCT clinical features (epilepsy and cognitive impairment)-had suboptimal outcomes. Loes scores stabilized/improved in four patients; GALC enzyme activity normalized in all. Electrophysiological measures mostly remained stable. HSCT significantly impacts the natural history of juvenile GLD, resulting in largely optimal long-term outcomes, preserved quality of life, and minimal disability. Standardized pre-transplant assessments are critical. High pre-HSCT Loes scores, epilepsy, and cognitive impairment could be prognostic indicators, highlighting the importance of early intervention based on comprehensive instrumental evaluations.
2026-01-08 | Caregiver-reported disease burden in Krabbe disease: evaluating outcomes of hematopoietic stem cell transplantation.
BACKGROUND: Krabbe disease (KD) is a rapidly progressive neurodegenerative disorder caused by β-galactocerebrosidase deficiency. While KD has been added to the Recommended Uniform Screening Panel (RUSP), only 15 states have an active KD newborn screening (NBS) program. It is uncertain at what rate states will adopt RUSP recommendations, with a frequently cited barrier being the absence of investigations addressing the impact of hematopoietic stem cell transplantation (HSCT) on quality-of-life. METHODS: We developed a 90-minute caregiver interview to gather qualitative and quantitative data (including the validated Leukodystrophy Quality-of-Life Assessment – LQLA) evaluating patient/family-centered outcomes of HSCT. The interview was designed to explore the following: 1) disease burden on the patient; 2) physical burden on the caregiver; and 3) emotional/social burden on the caregiver. Comparisons were made between children not transplanted/transplanted late and children transplanted early. Infantile KD (IKD) and late infantile KD (LIKD) were analyzed independently. RESULTS: Forty caregivers participated (non-transplanted/transplanted late: IKD = 19, LIKD = 7; transplanted early: IKD = 10, LIKD = 4). Analysis of the LQLA revealed a relative reduction in disease burden in both IKD and LIKD groups who were transplanted early. Specifically, the early transplanted cohorts achieved statistically significant higher overall scores on the LQLA, as well as better scores in various subcategories in comparison to their non-transplanted/transplanted late counterparts. For IKD, analysis of Likert scale and weighted analysis demonstrated a tendency towards decreased physical burden on caregivers of children transplanted early. Although all groups experienced significant social/emotional burdens, caregivers of IKD transplanted early benefitted from improved sleep, mental health, and familial/spousal relationships compared to IKD non-transplanted/transplanted late. CONCLUSION: This study provides convincing evidence that HSCT improves quality-of-life and reduces caregiver burden in IKD. The evidence is somewhat less clear for LIKD due to the small LIKD sample size. This data will be critical in the decision-making process for states not currently screening for KD but debating the addition of KD to their NBS panels. Lastly, it will allow families to weigh the risks and benefits of HSCT more confidently when contemplating the life-altering decision of whether to proceed with transplantation.
2025-12-01 | Inborn errors of metabolism and osteopetrosis
Allogeneic hematopoietic cell transplantation (HCT) remains the standard and potentially curative therapy for certain inborn errors of metabolism (IEM) and for osteopetrosis. This paper updates the Brazilian consensus guidelines for HCT indications in pediatric patients with IEM, specifically focusing on mucopolysaccharidosis, X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, and osteopetrosis. We emphasize the importance of early diagnosis, timely referral, and multidisciplinary follow-up to optimize patient outcomes. Additionally, we discuss the evolving landscape of conditioning regimens and donor selection criteria, underscoring the critical need for genetic testing to guide therapy. Future directions in research, including gene therapy and novel therapeutic strategies, are also highlighted.
gene therapies
2026-06-09 | Pediatrician Involvement in Communicating Positive Newborn Screening Results for Krabbe Disease: Barriers, Facilitators, and Ideas for Interventions (P4-8.002)
In this study, we aimed to understand pediatrics clinicians’ perspectives on barriers, facilitators, and ideas for interventions regarding their integration in disclosing positive NBS results for Krabbe disease.
2026-04-28 | Data from "A new CRISPR/Cas9 GALC Knockout cellular Model Reveals Lactosylceramide Accumulation Similar to Twitcher Mice."
Krabbe disease (KD) is a lysosomal sphingolipidosis caused by the deficiency of galactocerebrosidase (GALC), leading to profound alterations in sphingolipid metabolism and severe neurodegeneration. While psychosine (Psy) accumulation is a well-established hallmark of KD, emerging evidence suggests that lactosylceramide (LacCer) may also contribute to disease pathogenesis. Here, we generated a novel human oligodendrocytic model of GALC deficiency by CRISPR/Cas9-mediated GALC knockout in MO3.13 cells and used it to investigate sphingolipid alterations associated with impaired GALC activity. GALC−/− MO3.13 cells showed a marked reduction in GALC transcript levels and enzymatic activity, confirming the successful establishment of a disease-relevant cellular model. Our results demonstrated that a) GALC knockout MO3.13 cells accumulated Psy and LacCer, and b) LacCer content was increased in the brain and heart isolated from twitcher (TWI) mice, the most widely used spontaneous animal model of KD. In parallel, AKT signalling was evaluated in both systems, supporting a link between LacCer dysregulation and altered cellular signalling pathways. Overall, these findings identify LacCer accumulation as a conserved feature of GALC deficiency across cellular and animal models and support the use of GALC−/− MO3.13 cells as a novel in vitro platform to investigate KD pathogenesis and candidate therapeutic strategies.
2026-04-24 | In vivo adenine base editing of mutant Galc gene ameliorates Krabbe disease progression.
BACKGROUND: Krabbe disease (KD) is caused by mutation of the galactosylceramidase (GALC) gene, leading to deficient sphingolipid metabolism, which is essential for functional myelination. The twitcher (Galctwi/twi) mouse, a KD model with a premature termination codon (PTC) caused by a single-nucleotide G-to-A substitution at the 355th codon of the Galc gene, is a model candidate for treatment with adenine base editors (ABEs). ABEs have emerged exclusively among genome editing systems as viable therapeutic candidates to correct mutant genes. METHODS: To confirm base editing efficiency of ABEs, mouse embryonic fibroblasts (MEFs) or mutant GALC HEK293T cells treated with three ABE variants (ABEmax, ABE8eWQ, ABE8e) were assessed using targeted deep sequencing. Each split-ABE8e vector was packaged into a dual-vector adeno-associated virus serotype 9 (AAV9) system and delivered to twitcher mice via intracerebroventricular injection on postnatal day 1. Thereafter, motor functions and survival rate were evaluated by rotarod test, clasping test and lifespan analysis. Various methods, including next-generation sequencing (NGS), qRT-PCR, enzyme activity assay, and flow cytometry, were used to measure the base correction rate of the target gene and verified restoration of GALC enzyme activity in the brain of ABE8e-treated mice. Additionally, myelin recovery was evaluated in the brain using histological analysis, magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and transmission electron microscopy (TEM). RESULTS: The ABE8e-treated MEFs and mutant GALC HEK293T cells showed the most effective editing among the ABE variants tested. Three weeks after dual-AAV9 injection, the PTC was corrected in approximately 0.5% of genomic DNA and 5% of mRNA in twitcher mice. ABE8e treatment restored GALC enzymatic activity to approximately 5% of wild-type (WT) levels, while reducing the accumulation of psychosine—a major neurotoxic metabolite—by approximately 47% relative to WT. Moreover, histological analysis, TEM and, DTI and T2-weighted MRI showed preserved myelination and axonal integrity, along with amelioration of myelin deficits in the corpus callosum of ABE-treated twitcher mice. Five weeks after ABE8e administration, body weight recovered to approximately 64% of WT levels, accompanied by an extension of lifespan. In addition, clasping scores and rotarod performance improved to approximately 23% and 64% of WT levels, respectively. CONCLUSIONS: These data demonstrate a reliable application of base editing technology using ABEs as a potential treatment option for KD, progressing the development of therapeutics treating various genetic diseases.
2026-02-13 | Very late-onset Krabbe disease with concomitant dementia: case description and a critical review of the literature.
Krabbe disease (KD) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in GALC. Despite accounting only for 5% of forms, reports of adult-onset KD cases are increasingly described. A female patient manifesting KD after the age of 60 years, presenting with spastic paraplegia and cognitive decline, is described. The scientific literature of KD with onset > 10 years has been extensively reviewed to refine the spectrum of later-onset KD manifestations. Including ours, we identified 84 KD adolescent/adult-onset patients (mean age at onset 28.7 ± 14.2 years). Most patients had limb spasticity as main characterizing neurological feature (58/84, 70.2%), followed by polyneuropathy (11/ 84, 13.1%), both upper and lower motor neuron signs (2/84, 2.4%), and epilepsy (2/84, 2.4%). Five out of 84 patients (6.0%) were asymptomatic. Most patients had cortico-spinal tracts involvement at brain MRI. The most common pathogenic GALC variants were the c.1901 T > C (18 patients), the c.857G > A (13 patients), and the c.1161 + 6532_polyA + 9kbdel (13 patients). Complicated spastic paraplegia is the most common manifestation in later-onset KD, rarely with normal brain MRI. KD should be always considered also in cases with very late-onset spastic paraplegia. The online version contains supplementary material available at 10.1007/s10072-026-08836-5.
2026-02-09 | Brachial plexopathy in juvenile-onset Krabbe disease: A rare case.
Krabbe disease is an autosomal recessive leukodystrophy where a deficiency of the galactosylceramide beta-hydrolase enzyme leads to accumulation of toxic substances which cause demyelination in both central and peripheral nervous systems. It is classified into early infantile, late infantile, juvenile and adult types based on the age of presentation. MRI of the brain in patients with Krabbe disease shows bilaterally symmetrical T2 hyperintense signal in the periventricular and deep white matter and in the corticospinal tracts. Patients can have peripheral neuropathy, which, on imaging, is commonly seen in the form of thickening and enhancement of cranial nerves and nerve roots of cauda equina. Our patient, a child aged eleven years, had intracranial lesions along with brachial plexopathy. This is the first described case of juvenile-onset Krabbe disease with brachial plexus involvement.
small molecules
2026-08-13 | Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism
Krabbe disease is a rare autosomal recessive lysosomal disease caused by deficiency of galactocerebrosidase (GALC), leading to accumulation of galactosylceramide and formation of the toxic metabolite galactosylsphingosine (psychosine). While psychosine accumulation is well-established as a primary pathogenic mechanism, the broader metabolic consequences of GALC deficiency remain incompletely understood. In this study, we used stable isotope tracing to comprehensively characterize metabolic perturbations in a human oligodendrocellular Krabbe disease model. This approach revealed elevated de novo ceramide synthesis in GALC knock-out cells, characterized by increased incorporation of glucose-derived serine into ceramide biosynthetic pathways. This enhanced ceramide production was amenable to pharmacological intervention by tezacaftor, an inhibitor of sphingolipid Δ4-desaturate (DEGS); tezacaftor administration also normalized psychosine levels, raising the possibility of its use as substrate reduction therapy. Additionally, we identified significant disruption of UDP-hexose metabolism, manifesting as an overabundance of truncated and hypogalactosylated glycans. These findings suggest impaired protein glycosylation as a previously unrecognized pathogenic mechanism in Krabbe disease. Our findings reveal novel metabolic dysregulation in Krabbe disease extending beyond established psychosine toxicity. The identification of enhanced de novo ceramide synthesis presents a new therapeutic target, while the discovery of galactose-deficient glycosylation defects supports galactose supplementation as a potential therapeutic intervention. These metabolic insights provide new mechanistic understanding and therapeutic opportunities for this devastating neurodegenerative disorder.
2026-06-11 | Validating a Human Cell Model of Null Galactosylceramidase (GALC) Enzyme Activity That Recapitulates Krabbe Disease.
Krabbe Disease (KD) is a lysosomal leukodystrophy characterized by the production of psychosine in oligodendrocytes, leading to neurodegeneration and ultimately death. The only treatment modality currently available for this disease is hematopoietic stem cell transplantation (HSCT), a procedure with high morbidity, highlighting the need for further therapies to be developed. In this study, we established and characterized GALC knockout MO3.13 cells, a cell line derived from human oligodendrocytes, as a model for KD. Clonal MO3.13 cells with GALC KO were obtained via CRISPR/Cas9-mediated gene editing. GALC activity was measured by a 4-methylumbellyferyl (4-MU)-based assay, and morphology analyses were performed using light microscopy and transmission electron microscopy. Psychosine was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The GALC KO cells have elevated levels of psychosine and an increased number of autophagosomes, autolysosomes, and cytoplasmic granules on transmission electron microscopy. Glycogen abundance was decreased in GALC KO cells compared to controls. After administration of BMN-S202, a ceramide galactosyltransferase inhibitor, psychosine levels in GALC KO cells were reduced back to WT levels. In conclusion, we demonstrated that the GALC KO MO3.13 cell line recapitulates the KD phenotype and biochemical response to SRT and may be a useful KD model for mechanistic studies and therapeutic development for KD.
2026-02-26 | Sphingolipid-neutralizing molecular therapy reduces psychosine cytotoxicity in Krabbe disease.
The deficiency of β-galactosylceramidase causes a lysosomal leukodystrophy, known as Krabbe disease (KD), resulting in elevated psychosine (PSY) levels, which are highly cytotoxic to myelin-forming cells. 2-hydroxypropyl-α-CD (HPaCD), a cyclic-oligosaccharide containing a lipophilic central cavity and hydrophilic outer surfaces, significantly reduces PSY cytotoxicity in cultured KD patient cells. Further 1H-NMR studies revealed stronger interactions between HPaCD and PSY. Regarding safety, HPaCD-treated mice showed no electrophysiological and histological ototoxicity signs. In the murine KD model, HPaCD improved neurobehavior and reduced PSY levels in the CNS and PNS. The reduction of astrogliosis, increased myelin basic protein, and improvements in PNS axonal-myelin morphometrics were also observed in HPaCD-treated mice. In summary, this is an innovative therapeutic approach that leverages HPaCD's dual properties of molecularly shielding and neutralizing PSY and facilitating its CNS and PNS clearance. Since several newborn screening programs currently include KD, HPaCD becomes highly important as an adjunctive/bridge therapy for improving outcomes in this devastating disorder.
2025-07-03 | Self-Assembly of Accumulated Sphingolipids into Cytotoxic Fibrils in Globoid Cell Leukodystrophy and Their Inhibition by Small Molecules In Vitro.
Globoid cell leukodystrophy (GLD) is a rare hereditary inborn error of metabolism due to recessive mutations that cause loss of function of the enzyme galactosylceramidase (GALC). This results in the accumulation of the sphingolipids galactosylceramide (GalCer) and galactosylsphingosine (GalSph) in the lysosomes of neuronal cells. The accumulated GalCer and GalSph in cerebral macrophages of GLD patients are neurotoxic to oligodendrocytes and Schwann cells, leading to demyelination in the nervous system. The disease typically presents with infantile onset in the first six months of life and death by age 2. Here, we identified a supramolecular structure of GalCer and GalSph that may contribute to GLD pathology. Using biophysical assays commonly used for studying proteinaceous amyloids, e.g., amyloid-specific dyes, microscopical imaging, and a series of analytical methods (FTIR, PXRD, and SAXS), we demonstrate that both GalCer and GalSph can self-assemble in vitro into highly organized fibrils reminiscent of fibrils of amyloidogenic proteins. These fibrils exhibit significant cytotoxicity to both neuronal and oligodendroglial cells. Using an inhibitor of the GALC enzyme in cell culture to mimic the GLD pathophysiology, we could detect the accumulation of these fibrils in cells. We also observed that small molecules, which are bona fide inhibitors of proteinaceous amyloids, effectively mitigated the formation of the GalCer and GalSph fibrillar structures in vitro. Finally, the small molecule ameliorated the cytotoxic effects of the sphingolipid fibrils in SH-SY5Y cells, suggesting a potential avenue for therapeutic intervention in GLD orphan disease.
2025-06-01 | Quantification profiles of enzyme activity, secretion, and psychosine levels of Krabbe disease galactosylceramidase missense variants.
Krabbe disease is an autosomal recessive, demyelinating disorder caused by mutations in the GALC gene. Missense mutation variants (MMVs) account for most pathogenic alleles in patients; however, their mechanistic implications and correlations to clinical phenotype remain unclear. To address these questions, we generated a GALC knockout human oligodendrocytic cell line to conduct a robust GALC-MMVs expression study using a panel of 31 GALC-MMVs. Twenty-six clinically relevant variants dramatically reduced enzyme activity (92-100%). Notably, residual GALC activity strongly correlated with the age of disease-onset in reported cases (Pearson's r > 0.94, p < 0.0001), suggesting that enzyme activity resulting from MMV expression in this model may serve as a readout for clinical prognostication. In addition, we identified p.I562T, a predominant pseudodeficiency variant in the newborn screening programs, which synergistically impairs protein function and likely triggers disease-onset when inherited co-allelic with certain MMVs. We also identified MMVs that increased protein retention intracellularly and/or decreased secretion. This quantitative analysis of misfolding characteristics could be valuable for identifying MMVs amenable to pharmacological chaperone therapy. Finally, we observed an inverse correlation between residual GALC activity and endogenous psychosine levels in the MMV panel. Given the importance of psychosine as a biomarker for diagnosis and newborn screening, the psychosine accumulation phenotype in our model highlights its potential use for drug discovery. Overall, this study provides a comprehensive overview of the functional deficits and mis-trafficking caused by GALC-MMVs, deepens our understanding of molecular genetics and genotype-phenotype correlations in Krabbe disease, and highlights the potential of our platform for genetic and therapeutic applications.
proteins
2025-07-01 | Investigating the Cellular Effects of GALC Dosing in Enzyme Replacement Therapy for Krabbe Disease Supports the Role of Nanomedicine.
Krabbe disease (KD) is a lysosomal storage disorder characterized by severe neurodegeneration and demyelination. It is caused by mutations in the galactosylceramidase (GALC) gene, leading to the accumulation of psychosine, a neurotoxic metabolite. This study presents an optimized workflow for the production and characterization of recombinant murine GALC (rm-GALC) from HEK293T cells, aiming to improve the feasibility of enzyme replacement therapy (ERT) for KD. An affinity chromatography protocol is refined to purify His-tagged rm-GALC, followed by buffer exchange and concentration steps to produce a stable and active enzyme suitable for subsequent in vitro applications. The purified rm-GALC is characterized for enzymatic activity, purity, and stability using SDS-PAGE, immunoblotting, and dynamic light scattering (DLS). In vitro assays reveal dose-dependent enzymatic activity recovery in KD primary cells upon rm-GALC administration, with no adverse effects on cell viability up to the physiological GALC dose. Additionally, GALC treatment at the physiological dose restored autophagic function in KD cells, as shown by LC3 and p62 marker analyses, confirming its compatibility with lysosomal-autophagic pathways. Conversely, supra-physiological GALC administration resulted in decreased viability and autophagy impairment. Finally, the feasibility of loading GALC into a polymeric nanovector based on stabilized reverse micelles is investigated. These findings highlight the critical importance of precise GALC dose regulation in developing a safe and effective enzyme replacement therapy (ERT) strategy for Krabbe disease (KD), further supporting the potential of a nanovector-mediated ERT approach.
2022-08-21 | β-Galactosylceramidase Deficiency Causes Upregulation of Long Pentraxin-3 in the Central Nervous System of Krabbe Patients and Twitcher Mice
Globoid cell leukodystrophy (GLD), or Krabbe disease, is a neurodegenerative sphingolipidosis caused by genetic deficiency of lysosomal β-galactosylceramidase (GALC), characterized by neuroinflammation and demyelination of the central (CNS) and peripheral nervous system. The acute phase protein long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and a regulator of innate immunity. Growing evidence points to the involvement of PTX3 in neurodegeneration. However, the expression and role of PTX3 in the neurodegenerative/neuroinflammatory processes that characterize GLD remain unexplored. Here, immunohistochemical analysis of brain samples from Krabbe patients showed that macrophages and globoid cells are intensely immunoreactive for PTX3. Accordingly, Ptx3 expression increases throughout the course of the disease in the cerebrum, cerebellum, and spinal cord of GALC-deficient twitcher (Galctwi/twi) mice, an authentic animal model of GLD. This was paralleled by the upregulation of proinflammatory genes and M1-polarized macrophage/microglia markers and of the levels of PTX3 protein in CNS and plasma of twitcher animals. Crossing of Galctwi/twi mice with transgenic PTX3 overexpressing animals (hPTX3 mice) demonstrated that constitutive PTX3 overexpression reduced the severity of clinical signs and the upregulation of proinflammatory genes in the spinal cord of P35 hPTX3/Galctwi/twi mice when compared to Galctwi/twi littermates, leading to a limited increase of their life span. However, this occurred in the absence of a significant impact on the histopathological findings and on the accumulation of the neurotoxic metabolite psychosine when evaluated at this late time point of the disease. In conclusion, our results provide the first evidence that PTX3 is produced in the CNS of GALC-deficient Krabbe patients and twitcher mice. PTX3 may exert a protective role by reducing the neuroinflammatory response that occurs in the spinal cord of GALC-deficient animals.
2021-07-05 | Therapeutic Uses of Bacterial Subunit Toxins.
The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb3) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin-receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb3 (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb3 is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb3 is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb3 levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb3 is upregulated in the neovasculature of many tumours, irrespective of tumour Gb3 status. Gb3 is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented.
2021-06-28 | Molecular dynamics simulations to decipher the structural and functional consequences of pathogenic missense mutations in the galactosylceramidase (GALC) protein causing Krabbe's disease.
Krabbe disease (KD), also known as globoid cell leukodystrophy disease, is an autosomal recessive lysosomal storage genetic disorder, which is caused by the deficiency of galactocerebrosidase (GALC) coding gene (GALC). This study aimed to use extensive computational pipelines in understanding the missense mutations in GALC. We retrieved 176 mutations from the public databases and subjected them to pathogenicity, stability, and conservation analyses. The PredictSNP, iStable, and ConSurf prediction tools predicted 45, 95, and 47 mutations to be deleterious, destabilizing, and highly conserved, respectively. The R396L and R396W were the most deleterious and destabilizing to GALC, and were therefore prioritized for further analysis. Systematic validation on the impact of the R396L and R396W mutations to the chaperone alpha lobeline was performed using the molecular docking approach. The docking analysis revealed that the mutant R396W interacted with minimal binding affinity compared with both the R396L mutant and native GALC. Furthermore, the repetitive molecular dynamics simulation analysis showed that the mutant R396W demonstrated less compactness and reduced number of intramolecular hydrogen bonds compared with the mutant R396L and the native GALC. Overall, we observed higher structural and functional modifications in R396W positioned in the substrate-binding site. This was highly supported by the MMPBSA and DSSP analysis of the GROMACS. DSSP showed the transformation of turns to bends, indicating a loss of stability due to the R396W mutation. This study is expected to serve as a platform for prioritizing mutant proteins that could be a platform for both drug and target therapeuticsCommunicated by Ramaswamy H. Sarma.
2020-07-27 | Cell-autonomous expression of the acid hydrolase galactocerebrosidase.
Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease.
other
2025-03-10 | Neuroimmunology in globoid cell leukodystrophy: A comprehensive review including treatments, models, and neuroimmune mechanisms underlying neuropathology.
Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a fatal genetic demyelinating disease of the central nervous system (CNS) caused by loss-of-function mutations in galactosylceramidase (GALC). As a result of the loss of GALC enzymatic activity, there is an accumulation of a toxic lipid called galactosylsphingosine, or psychosine. Current treatments have focused on restoring GALC function as a means to reduce psychosine accumulation, which show promise, however, still have limited success at improving behavioral or cognitive deficits in infants with GLD. Recent studies have discovered a role for T cells in GLD, indicating that there is a previously understudied role for the adaptive immune system as a contributing factor to GLD pathophysiology. This review aims to provide a comprehensive discussion of the current field of GLD research including treatment advances and GLD pathophysiology, with a focus on the role of neuroimmunological mechanisms contributing to GLD.
2023-06-13 | CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy
Globoid cell leukodystrophy (GLD) or Krabbe’s disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein, we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD. Administration of a function-blocking antibody against CD8α effectively prevented disease onset, reduced morbidity and mortality, and prevented CNS demyelination in mice. These data indicate that subsequent to the genetic cause of disease, neuropathology is driven by pathogenic CD8+ T cells, thus offering novel therapeutic potential for treatment of GLD.
2022-10-03 | Therapeutic depletion of CD8+ T-cells prevents myelin pathology in Globoid Cell Leukodystrophy
Abstract Globoid cell leukodystrophy (GLD) or Krabbe’s disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD. Administration of a function blocking antibody against CD8α effectively prevented disease onset, reduced morbidity and mortality and prevented CNS demyelination in mice. These data indicate that subsequent to the genetic cause of disease, neuropathology is driven by pathogenic CD8+ T cells, thus offering novel therapeutic potential for treatment of GLD. One-Sentence Summary CD8 T-cells mediate demyelination and neuroinflammation in a genetic white matter disease.
2021-04-16 | Adult Krabbe Disease That Was Successfully Treated with Intravenous Immunoglobulin.
Krabbe disease involves the accumulation of neurotoxic metabolites due to lysosomal galactocerebrosidase enzyme deficiency, which results in widespread demyelination of central and peripheral nerves. Generally, Krabbe disease presents as spastic paraplegia with a slow progressive course; however, some cases may show clinical symptoms similar to those of chronic inflammatory demyelinating polyneuropathy (CIDP). No previously reported studies have investigated the efficacy of intravenous immunoglobulin (IVIg) for treating Krabbe disease, and reporting a case involving IVIg treatment may be informative in the clinical setting. A 14-year-old girl who developed Guillain-Barré syndrome-like limb weakness was administered IVIg, and her limb weakness improved. At 16 years old, she developed abnormal sensory perception and weakness of both upper limbs. A nerve conduction study revealed demyelination, which led us to suspect CIDP. IVIg was administered, and her symptoms gradually improved. A nerve biopsy, enzyme activity, and genetic test results indicated adult Krabbe disease. In some cases, IVIg may be an effective treatment for Krabbe disease.
2006-10-25 | Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice
PLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants with RAG-1-deficient mice lacking mature lymphocytes, we could recently demonstrate a pathogenetic impact of the CD8+ cells. In the present study, we investigated the pathogenetic impact of CD11b+ macrophages by crossbreeding the myelin mutants with knockout mice deficient for the macrophage-restricted adhesion molecule sialoadhesin (Sn). In the wild-type mice, Sn is barely detectable on CD11b+ cells, whereas in the myelin mutants, almost all CD11b+ cells express Sn. In the double mutants, upregulation of CD8+ T-cells and CD11b+ macrophages is reduced and pathological alterations are ameliorated. These data indicate that in a primarily genetically caused myelin disorder of the CNS macrophages expressing Sn partially mediate pathogenesis. These findings may have substantial impact on treatment strategies for leukodystrophic disorders and some forms of multiple sclerosis.
cell therapies
2026-08-13 | Survival benefit and immune-related toxicities after hematopoietic stem cell transplantation in Krabbe disease: a systematic review and meta-analysis
Background Krabbe disease is a rare, rapidly progressive leukodystrophy with high early mortality. Hematopoietic stem cell transplantation (HSCT) is the main disease-modifying intervention used in clinical practice and may act through donor-derived myeloid and immune-cell replacement, enzymatic cross-correction, and immunomodulation. However, its benefits and immune-related toxicities remain incompletely quantified. Methods We conducted a systematic review and meta-analysis of studies reporting HSCT outcomes in genetically or enzymatically confirmed Krabbe disease. The primary outcome was overall survival (OS). Secondary outcomes included 5-year OS, transplant-related mortality (TRM), acute and chronic graft-versus-host disease (aGVHD and cGVHD), neurological stability, and MRI stability. For OS, publication bias or small-study effects were assessed using funnel-plot inspection and Egger’s regression test. Exploratory univariable meta-regression examined total study sample size, publication year, and Newcastle–Ottawa Scale (NOS) score, and robustness was assessed using leave-one-out sensitivity analysis. Results Fifteen studies involving 141 patients were included. Pooled OS after HSCT was 84% (95% CI, 75%–93%), 5-year OS was 80% (69%–92%), and TRM was 7% (1%–13%). The pooled incidences of aGVHD and cGVHD were 53% (16%–90%) and 25% (0%–53%), respectively. Neurological stability was reported in only four studies including 15 patients (77%; 31%–100%), and MRI stability in four studies including 32 patients (49%; 7%–90%); both estimates showed substantial heterogeneity and wide confidence intervals. Subgroup analyses by disease-onset age, pre-transplant symptom status, and age at HSCT showed no statistically significant OS differences. Egger’s test detected no significant funnel-plot asymmetry (P = 0.569). Leave-one-out estimates ranged from 82% to 86%. Meta-regression showed inverse associations of reported OS with total study sample size and NOS score (both P < 0.001), whereas publication year was not significant (P = 0.118). Conclusion HSCT is associated with favorable survival and relatively low pooled TRM in selected patients with Krabbe disease. However, survival should not be interpreted as preservation of neurological function, because neurological, MRI, and GVHD outcomes were reported in few studies and patients and remained heterogeneous and imprecisely estimated. These findings require cautious interpretation but provide clinically useful benchmark data for counseling and comparison with emerging cellular and gene-based therapies. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261285624.
2026-04-23 | Stem cell therapy for rare neurological diseases: translational research opportunities
Stem cell therapy is being explored for several rare neurological conditions in humans given their potential immunomodulatory, reparative, and regenerative capabilities. Existing standard treatments for most neuroinflammatory and neurodegenerative disorders are primarily palliative, focusing on symptom management rather than addressing underlying disease pathology. The genetic and pathophysiological parallels between many human and animal neurological diseases suggest that companion animals may serve as valuable translational models to drive stem cell research forward. Several rare human neurological conditions with companion animal (particularly canine) correlates include fulminant multiple sclerosis (MS), myasthenia gravis, amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Dravet and Lennox-Gastaut Syndromes, Globoid Cell Leukodystrophy/Krabbe Disease, viral encephalitis, and glioblastoma multiforme (GBM). Validating the safety and feasibility of stem cell transplantation in companion animal models has enabled the development and expansion of innovative therapies. Stem cell therapy may hold promise as a novel treatment option for some rare and aggressive human and companion animal neurological diseases with limited treatment options.
2026-01-28 | Long-term neurological outcome after hematopoietic stem cell transplant in juvenile Krabbe disease.
Globoid cell leukodystrophy (GLD) is a progressive neurodegenerative disease caused by galactocerebrosidase deficiency. Juvenile phenotypes-onset between ages 3 and 16-account for up to 25% of cases. Hematopoietic stem cell transplantation (HSCT) is the only available treatment, yet only eight juvenile-onset cases treated with HSCT have been reported, with heterogeneously collected data. We aim to comprehensively evaluate long-term neurological outcomes post-HSCT in juvenile GLD. We conducted a retrospective study of all juvenile GLD patients treated with HSCT and followed at our Institution. We assessed survival, neurological status, disability (modified Rankin Scale), cognitive outcomes, GALC activity, serial MRIs (Loes score), evoked potentials (internal scoring system), and nerve conduction studies at pre-HSCT, first post-HSCT visit, and last follow-up. Six biochemically and genetically confirmed juvenile GLD cases were included. Four were symptomatic at diagnosis; two were pre-symptomatic. All survived to last follow-up (range 9 years, 2 months-19 years, and 8 months). Four achieved near-normal cognitive, motor, and functional status. Two symptomatic patients-with extensive pre-HSCT white matter disease and specific pre-HSCT clinical features (epilepsy and cognitive impairment)-had suboptimal outcomes. Loes scores stabilized/improved in four patients; GALC enzyme activity normalized in all. Electrophysiological measures mostly remained stable. HSCT significantly impacts the natural history of juvenile GLD, resulting in largely optimal long-term outcomes, preserved quality of life, and minimal disability. Standardized pre-transplant assessments are critical. High pre-HSCT Loes scores, epilepsy, and cognitive impairment could be prognostic indicators, highlighting the importance of early intervention based on comprehensive instrumental evaluations.
2026-01-08 | Caregiver-reported disease burden in Krabbe disease: evaluating outcomes of hematopoietic stem cell transplantation.
BACKGROUND: Krabbe disease (KD) is a rapidly progressive neurodegenerative disorder caused by β-galactocerebrosidase deficiency. While KD has been added to the Recommended Uniform Screening Panel (RUSP), only 15 states have an active KD newborn screening (NBS) program. It is uncertain at what rate states will adopt RUSP recommendations, with a frequently cited barrier being the absence of investigations addressing the impact of hematopoietic stem cell transplantation (HSCT) on quality-of-life. METHODS: We developed a 90-minute caregiver interview to gather qualitative and quantitative data (including the validated Leukodystrophy Quality-of-Life Assessment – LQLA) evaluating patient/family-centered outcomes of HSCT. The interview was designed to explore the following: 1) disease burden on the patient; 2) physical burden on the caregiver; and 3) emotional/social burden on the caregiver. Comparisons were made between children not transplanted/transplanted late and children transplanted early. Infantile KD (IKD) and late infantile KD (LIKD) were analyzed independently. RESULTS: Forty caregivers participated (non-transplanted/transplanted late: IKD = 19, LIKD = 7; transplanted early: IKD = 10, LIKD = 4). Analysis of the LQLA revealed a relative reduction in disease burden in both IKD and LIKD groups who were transplanted early. Specifically, the early transplanted cohorts achieved statistically significant higher overall scores on the LQLA, as well as better scores in various subcategories in comparison to their non-transplanted/transplanted late counterparts. For IKD, analysis of Likert scale and weighted analysis demonstrated a tendency towards decreased physical burden on caregivers of children transplanted early. Although all groups experienced significant social/emotional burdens, caregivers of IKD transplanted early benefitted from improved sleep, mental health, and familial/spousal relationships compared to IKD non-transplanted/transplanted late. CONCLUSION: This study provides convincing evidence that HSCT improves quality-of-life and reduces caregiver burden in IKD. The evidence is somewhat less clear for LIKD due to the small LIKD sample size. This data will be critical in the decision-making process for states not currently screening for KD but debating the addition of KD to their NBS panels. Lastly, it will allow families to weigh the risks and benefits of HSCT more confidently when contemplating the life-altering decision of whether to proceed with transplantation.
2025-12-01 | Inborn errors of metabolism and osteopetrosis
Allogeneic hematopoietic cell transplantation (HCT) remains the standard and potentially curative therapy for certain inborn errors of metabolism (IEM) and for osteopetrosis. This paper updates the Brazilian consensus guidelines for HCT indications in pediatric patients with IEM, specifically focusing on mucopolysaccharidosis, X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, and osteopetrosis. We emphasize the importance of early diagnosis, timely referral, and multidisciplinary follow-up to optimize patient outcomes. Additionally, we discuss the evolving landscape of conditioning regimens and donor selection criteria, underscoring the critical need for genetic testing to guide therapy. Future directions in research, including gene therapy and novel therapeutic strategies, are also highlighted.
gene therapies
2026-06-09 | Pediatrician Involvement in Communicating Positive Newborn Screening Results for Krabbe Disease: Barriers, Facilitators, and Ideas for Interventions (P4-8.002)
In this study, we aimed to understand pediatrics clinicians’ perspectives on barriers, facilitators, and ideas for interventions regarding their integration in disclosing positive NBS results for Krabbe disease.
2026-04-28 | Data from "A new CRISPR/Cas9 GALC Knockout cellular Model Reveals Lactosylceramide Accumulation Similar to Twitcher Mice."
Krabbe disease (KD) is a lysosomal sphingolipidosis caused by the deficiency of galactocerebrosidase (GALC), leading to profound alterations in sphingolipid metabolism and severe neurodegeneration. While psychosine (Psy) accumulation is a well-established hallmark of KD, emerging evidence suggests that lactosylceramide (LacCer) may also contribute to disease pathogenesis. Here, we generated a novel human oligodendrocytic model of GALC deficiency by CRISPR/Cas9-mediated GALC knockout in MO3.13 cells and used it to investigate sphingolipid alterations associated with impaired GALC activity. GALC−/− MO3.13 cells showed a marked reduction in GALC transcript levels and enzymatic activity, confirming the successful establishment of a disease-relevant cellular model. Our results demonstrated that a) GALC knockout MO3.13 cells accumulated Psy and LacCer, and b) LacCer content was increased in the brain and heart isolated from twitcher (TWI) mice, the most widely used spontaneous animal model of KD. In parallel, AKT signalling was evaluated in both systems, supporting a link between LacCer dysregulation and altered cellular signalling pathways. Overall, these findings identify LacCer accumulation as a conserved feature of GALC deficiency across cellular and animal models and support the use of GALC−/− MO3.13 cells as a novel in vitro platform to investigate KD pathogenesis and candidate therapeutic strategies.
2026-04-24 | In vivo adenine base editing of mutant Galc gene ameliorates Krabbe disease progression.
BACKGROUND: Krabbe disease (KD) is caused by mutation of the galactosylceramidase (GALC) gene, leading to deficient sphingolipid metabolism, which is essential for functional myelination. The twitcher (Galctwi/twi) mouse, a KD model with a premature termination codon (PTC) caused by a single-nucleotide G-to-A substitution at the 355th codon of the Galc gene, is a model candidate for treatment with adenine base editors (ABEs). ABEs have emerged exclusively among genome editing systems as viable therapeutic candidates to correct mutant genes. METHODS: To confirm base editing efficiency of ABEs, mouse embryonic fibroblasts (MEFs) or mutant GALC HEK293T cells treated with three ABE variants (ABEmax, ABE8eWQ, ABE8e) were assessed using targeted deep sequencing. Each split-ABE8e vector was packaged into a dual-vector adeno-associated virus serotype 9 (AAV9) system and delivered to twitcher mice via intracerebroventricular injection on postnatal day 1. Thereafter, motor functions and survival rate were evaluated by rotarod test, clasping test and lifespan analysis. Various methods, including next-generation sequencing (NGS), qRT-PCR, enzyme activity assay, and flow cytometry, were used to measure the base correction rate of the target gene and verified restoration of GALC enzyme activity in the brain of ABE8e-treated mice. Additionally, myelin recovery was evaluated in the brain using histological analysis, magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and transmission electron microscopy (TEM). RESULTS: The ABE8e-treated MEFs and mutant GALC HEK293T cells showed the most effective editing among the ABE variants tested. Three weeks after dual-AAV9 injection, the PTC was corrected in approximately 0.5% of genomic DNA and 5% of mRNA in twitcher mice. ABE8e treatment restored GALC enzymatic activity to approximately 5% of wild-type (WT) levels, while reducing the accumulation of psychosine—a major neurotoxic metabolite—by approximately 47% relative to WT. Moreover, histological analysis, TEM and, DTI and T2-weighted MRI showed preserved myelination and axonal integrity, along with amelioration of myelin deficits in the corpus callosum of ABE-treated twitcher mice. Five weeks after ABE8e administration, body weight recovered to approximately 64% of WT levels, accompanied by an extension of lifespan. In addition, clasping scores and rotarod performance improved to approximately 23% and 64% of WT levels, respectively. CONCLUSIONS: These data demonstrate a reliable application of base editing technology using ABEs as a potential treatment option for KD, progressing the development of therapeutics treating various genetic diseases.
2026-02-13 | Very late-onset Krabbe disease with concomitant dementia: case description and a critical review of the literature.
Krabbe disease (KD) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in GALC. Despite accounting only for 5% of forms, reports of adult-onset KD cases are increasingly described. A female patient manifesting KD after the age of 60 years, presenting with spastic paraplegia and cognitive decline, is described. The scientific literature of KD with onset > 10 years has been extensively reviewed to refine the spectrum of later-onset KD manifestations. Including ours, we identified 84 KD adolescent/adult-onset patients (mean age at onset 28.7 ± 14.2 years). Most patients had limb spasticity as main characterizing neurological feature (58/84, 70.2%), followed by polyneuropathy (11/ 84, 13.1%), both upper and lower motor neuron signs (2/84, 2.4%), and epilepsy (2/84, 2.4%). Five out of 84 patients (6.0%) were asymptomatic. Most patients had cortico-spinal tracts involvement at brain MRI. The most common pathogenic GALC variants were the c.1901 T > C (18 patients), the c.857G > A (13 patients), and the c.1161 + 6532_polyA + 9kbdel (13 patients). Complicated spastic paraplegia is the most common manifestation in later-onset KD, rarely with normal brain MRI. KD should be always considered also in cases with very late-onset spastic paraplegia. The online version contains supplementary material available at 10.1007/s10072-026-08836-5.
2026-02-09 | Brachial plexopathy in juvenile-onset Krabbe disease: A rare case.
Krabbe disease is an autosomal recessive leukodystrophy where a deficiency of the galactosylceramide beta-hydrolase enzyme leads to accumulation of toxic substances which cause demyelination in both central and peripheral nervous systems. It is classified into early infantile, late infantile, juvenile and adult types based on the age of presentation. MRI of the brain in patients with Krabbe disease shows bilaterally symmetrical T2 hyperintense signal in the periventricular and deep white matter and in the corticospinal tracts. Patients can have peripheral neuropathy, which, on imaging, is commonly seen in the form of thickening and enhancement of cranial nerves and nerve roots of cauda equina. Our patient, a child aged eleven years, had intracranial lesions along with brachial plexopathy. This is the first described case of juvenile-onset Krabbe disease with brachial plexus involvement.
small molecules
2026-08-13 | Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism
Krabbe disease is a rare autosomal recessive lysosomal disease caused by deficiency of galactocerebrosidase (GALC), leading to accumulation of galactosylceramide and formation of the toxic metabolite galactosylsphingosine (psychosine). While psychosine accumulation is well-established as a primary pathogenic mechanism, the broader metabolic consequences of GALC deficiency remain incompletely understood. In this study, we used stable isotope tracing to comprehensively characterize metabolic perturbations in a human oligodendrocellular Krabbe disease model. This approach revealed elevated de novo ceramide synthesis in GALC knock-out cells, characterized by increased incorporation of glucose-derived serine into ceramide biosynthetic pathways. This enhanced ceramide production was amenable to pharmacological intervention by tezacaftor, an inhibitor of sphingolipid Δ4-desaturate (DEGS); tezacaftor administration also normalized psychosine levels, raising the possibility of its use as substrate reduction therapy. Additionally, we identified significant disruption of UDP-hexose metabolism, manifesting as an overabundance of truncated and hypogalactosylated glycans. These findings suggest impaired protein glycosylation as a previously unrecognized pathogenic mechanism in Krabbe disease. Our findings reveal novel metabolic dysregulation in Krabbe disease extending beyond established psychosine toxicity. The identification of enhanced de novo ceramide synthesis presents a new therapeutic target, while the discovery of galactose-deficient glycosylation defects supports galactose supplementation as a potential therapeutic intervention. These metabolic insights provide new mechanistic understanding and therapeutic opportunities for this devastating neurodegenerative disorder.
2026-06-11 | Validating a Human Cell Model of Null Galactosylceramidase (GALC) Enzyme Activity That Recapitulates Krabbe Disease.
Krabbe Disease (KD) is a lysosomal leukodystrophy characterized by the production of psychosine in oligodendrocytes, leading to neurodegeneration and ultimately death. The only treatment modality currently available for this disease is hematopoietic stem cell transplantation (HSCT), a procedure with high morbidity, highlighting the need for further therapies to be developed. In this study, we established and characterized GALC knockout MO3.13 cells, a cell line derived from human oligodendrocytes, as a model for KD. Clonal MO3.13 cells with GALC KO were obtained via CRISPR/Cas9-mediated gene editing. GALC activity was measured by a 4-methylumbellyferyl (4-MU)-based assay, and morphology analyses were performed using light microscopy and transmission electron microscopy. Psychosine was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The GALC KO cells have elevated levels of psychosine and an increased number of autophagosomes, autolysosomes, and cytoplasmic granules on transmission electron microscopy. Glycogen abundance was decreased in GALC KO cells compared to controls. After administration of BMN-S202, a ceramide galactosyltransferase inhibitor, psychosine levels in GALC KO cells were reduced back to WT levels. In conclusion, we demonstrated that the GALC KO MO3.13 cell line recapitulates the KD phenotype and biochemical response to SRT and may be a useful KD model for mechanistic studies and therapeutic development for KD.
2026-02-26 | Sphingolipid-neutralizing molecular therapy reduces psychosine cytotoxicity in Krabbe disease.
The deficiency of β-galactosylceramidase causes a lysosomal leukodystrophy, known as Krabbe disease (KD), resulting in elevated psychosine (PSY) levels, which are highly cytotoxic to myelin-forming cells. 2-hydroxypropyl-α-CD (HPaCD), a cyclic-oligosaccharide containing a lipophilic central cavity and hydrophilic outer surfaces, significantly reduces PSY cytotoxicity in cultured KD patient cells. Further 1H-NMR studies revealed stronger interactions between HPaCD and PSY. Regarding safety, HPaCD-treated mice showed no electrophysiological and histological ototoxicity signs. In the murine KD model, HPaCD improved neurobehavior and reduced PSY levels in the CNS and PNS. The reduction of astrogliosis, increased myelin basic protein, and improvements in PNS axonal-myelin morphometrics were also observed in HPaCD-treated mice. In summary, this is an innovative therapeutic approach that leverages HPaCD's dual properties of molecularly shielding and neutralizing PSY and facilitating its CNS and PNS clearance. Since several newborn screening programs currently include KD, HPaCD becomes highly important as an adjunctive/bridge therapy for improving outcomes in this devastating disorder.
2025-07-03 | Self-Assembly of Accumulated Sphingolipids into Cytotoxic Fibrils in Globoid Cell Leukodystrophy and Their Inhibition by Small Molecules In Vitro.
Globoid cell leukodystrophy (GLD) is a rare hereditary inborn error of metabolism due to recessive mutations that cause loss of function of the enzyme galactosylceramidase (GALC). This results in the accumulation of the sphingolipids galactosylceramide (GalCer) and galactosylsphingosine (GalSph) in the lysosomes of neuronal cells. The accumulated GalCer and GalSph in cerebral macrophages of GLD patients are neurotoxic to oligodendrocytes and Schwann cells, leading to demyelination in the nervous system. The disease typically presents with infantile onset in the first six months of life and death by age 2. Here, we identified a supramolecular structure of GalCer and GalSph that may contribute to GLD pathology. Using biophysical assays commonly used for studying proteinaceous amyloids, e.g., amyloid-specific dyes, microscopical imaging, and a series of analytical methods (FTIR, PXRD, and SAXS), we demonstrate that both GalCer and GalSph can self-assemble in vitro into highly organized fibrils reminiscent of fibrils of amyloidogenic proteins. These fibrils exhibit significant cytotoxicity to both neuronal and oligodendroglial cells. Using an inhibitor of the GALC enzyme in cell culture to mimic the GLD pathophysiology, we could detect the accumulation of these fibrils in cells. We also observed that small molecules, which are bona fide inhibitors of proteinaceous amyloids, effectively mitigated the formation of the GalCer and GalSph fibrillar structures in vitro. Finally, the small molecule ameliorated the cytotoxic effects of the sphingolipid fibrils in SH-SY5Y cells, suggesting a potential avenue for therapeutic intervention in GLD orphan disease.
2025-06-01 | Quantification profiles of enzyme activity, secretion, and psychosine levels of Krabbe disease galactosylceramidase missense variants.
Krabbe disease is an autosomal recessive, demyelinating disorder caused by mutations in the GALC gene. Missense mutation variants (MMVs) account for most pathogenic alleles in patients; however, their mechanistic implications and correlations to clinical phenotype remain unclear. To address these questions, we generated a GALC knockout human oligodendrocytic cell line to conduct a robust GALC-MMVs expression study using a panel of 31 GALC-MMVs. Twenty-six clinically relevant variants dramatically reduced enzyme activity (92-100%). Notably, residual GALC activity strongly correlated with the age of disease-onset in reported cases (Pearson's r > 0.94, p < 0.0001), suggesting that enzyme activity resulting from MMV expression in this model may serve as a readout for clinical prognostication. In addition, we identified p.I562T, a predominant pseudodeficiency variant in the newborn screening programs, which synergistically impairs protein function and likely triggers disease-onset when inherited co-allelic with certain MMVs. We also identified MMVs that increased protein retention intracellularly and/or decreased secretion. This quantitative analysis of misfolding characteristics could be valuable for identifying MMVs amenable to pharmacological chaperone therapy. Finally, we observed an inverse correlation between residual GALC activity and endogenous psychosine levels in the MMV panel. Given the importance of psychosine as a biomarker for diagnosis and newborn screening, the psychosine accumulation phenotype in our model highlights its potential use for drug discovery. Overall, this study provides a comprehensive overview of the functional deficits and mis-trafficking caused by GALC-MMVs, deepens our understanding of molecular genetics and genotype-phenotype correlations in Krabbe disease, and highlights the potential of our platform for genetic and therapeutic applications.
proteins
2025-07-01 | Investigating the Cellular Effects of GALC Dosing in Enzyme Replacement Therapy for Krabbe Disease Supports the Role of Nanomedicine.
Krabbe disease (KD) is a lysosomal storage disorder characterized by severe neurodegeneration and demyelination. It is caused by mutations in the galactosylceramidase (GALC) gene, leading to the accumulation of psychosine, a neurotoxic metabolite. This study presents an optimized workflow for the production and characterization of recombinant murine GALC (rm-GALC) from HEK293T cells, aiming to improve the feasibility of enzyme replacement therapy (ERT) for KD. An affinity chromatography protocol is refined to purify His-tagged rm-GALC, followed by buffer exchange and concentration steps to produce a stable and active enzyme suitable for subsequent in vitro applications. The purified rm-GALC is characterized for enzymatic activity, purity, and stability using SDS-PAGE, immunoblotting, and dynamic light scattering (DLS). In vitro assays reveal dose-dependent enzymatic activity recovery in KD primary cells upon rm-GALC administration, with no adverse effects on cell viability up to the physiological GALC dose. Additionally, GALC treatment at the physiological dose restored autophagic function in KD cells, as shown by LC3 and p62 marker analyses, confirming its compatibility with lysosomal-autophagic pathways. Conversely, supra-physiological GALC administration resulted in decreased viability and autophagy impairment. Finally, the feasibility of loading GALC into a polymeric nanovector based on stabilized reverse micelles is investigated. These findings highlight the critical importance of precise GALC dose regulation in developing a safe and effective enzyme replacement therapy (ERT) strategy for Krabbe disease (KD), further supporting the potential of a nanovector-mediated ERT approach.
2022-08-21 | β-Galactosylceramidase Deficiency Causes Upregulation of Long Pentraxin-3 in the Central Nervous System of Krabbe Patients and Twitcher Mice
Globoid cell leukodystrophy (GLD), or Krabbe disease, is a neurodegenerative sphingolipidosis caused by genetic deficiency of lysosomal β-galactosylceramidase (GALC), characterized by neuroinflammation and demyelination of the central (CNS) and peripheral nervous system. The acute phase protein long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and a regulator of innate immunity. Growing evidence points to the involvement of PTX3 in neurodegeneration. However, the expression and role of PTX3 in the neurodegenerative/neuroinflammatory processes that characterize GLD remain unexplored. Here, immunohistochemical analysis of brain samples from Krabbe patients showed that macrophages and globoid cells are intensely immunoreactive for PTX3. Accordingly, Ptx3 expression increases throughout the course of the disease in the cerebrum, cerebellum, and spinal cord of GALC-deficient twitcher (Galctwi/twi) mice, an authentic animal model of GLD. This was paralleled by the upregulation of proinflammatory genes and M1-polarized macrophage/microglia markers and of the levels of PTX3 protein in CNS and plasma of twitcher animals. Crossing of Galctwi/twi mice with transgenic PTX3 overexpressing animals (hPTX3 mice) demonstrated that constitutive PTX3 overexpression reduced the severity of clinical signs and the upregulation of proinflammatory genes in the spinal cord of P35 hPTX3/Galctwi/twi mice when compared to Galctwi/twi littermates, leading to a limited increase of their life span. However, this occurred in the absence of a significant impact on the histopathological findings and on the accumulation of the neurotoxic metabolite psychosine when evaluated at this late time point of the disease. In conclusion, our results provide the first evidence that PTX3 is produced in the CNS of GALC-deficient Krabbe patients and twitcher mice. PTX3 may exert a protective role by reducing the neuroinflammatory response that occurs in the spinal cord of GALC-deficient animals.
2021-07-05 | Therapeutic Uses of Bacterial Subunit Toxins.
The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb3) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin-receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb3 (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb3 is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb3 is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb3 levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb3 is upregulated in the neovasculature of many tumours, irrespective of tumour Gb3 status. Gb3 is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented.
2021-06-28 | Molecular dynamics simulations to decipher the structural and functional consequences of pathogenic missense mutations in the galactosylceramidase (GALC) protein causing Krabbe's disease.
Krabbe disease (KD), also known as globoid cell leukodystrophy disease, is an autosomal recessive lysosomal storage genetic disorder, which is caused by the deficiency of galactocerebrosidase (GALC) coding gene (GALC). This study aimed to use extensive computational pipelines in understanding the missense mutations in GALC. We retrieved 176 mutations from the public databases and subjected them to pathogenicity, stability, and conservation analyses. The PredictSNP, iStable, and ConSurf prediction tools predicted 45, 95, and 47 mutations to be deleterious, destabilizing, and highly conserved, respectively. The R396L and R396W were the most deleterious and destabilizing to GALC, and were therefore prioritized for further analysis. Systematic validation on the impact of the R396L and R396W mutations to the chaperone alpha lobeline was performed using the molecular docking approach. The docking analysis revealed that the mutant R396W interacted with minimal binding affinity compared with both the R396L mutant and native GALC. Furthermore, the repetitive molecular dynamics simulation analysis showed that the mutant R396W demonstrated less compactness and reduced number of intramolecular hydrogen bonds compared with the mutant R396L and the native GALC. Overall, we observed higher structural and functional modifications in R396W positioned in the substrate-binding site. This was highly supported by the MMPBSA and DSSP analysis of the GROMACS. DSSP showed the transformation of turns to bends, indicating a loss of stability due to the R396W mutation. This study is expected to serve as a platform for prioritizing mutant proteins that could be a platform for both drug and target therapeuticsCommunicated by Ramaswamy H. Sarma.
2020-07-27 | Cell-autonomous expression of the acid hydrolase galactocerebrosidase.
Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease.
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2025-03-10 | Neuroimmunology in globoid cell leukodystrophy: A comprehensive review including treatments, models, and neuroimmune mechanisms underlying neuropathology.
Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a fatal genetic demyelinating disease of the central nervous system (CNS) caused by loss-of-function mutations in galactosylceramidase (GALC). As a result of the loss of GALC enzymatic activity, there is an accumulation of a toxic lipid called galactosylsphingosine, or psychosine. Current treatments have focused on restoring GALC function as a means to reduce psychosine accumulation, which show promise, however, still have limited success at improving behavioral or cognitive deficits in infants with GLD. Recent studies have discovered a role for T cells in GLD, indicating that there is a previously understudied role for the adaptive immune system as a contributing factor to GLD pathophysiology. This review aims to provide a comprehensive discussion of the current field of GLD research including treatment advances and GLD pathophysiology, with a focus on the role of neuroimmunological mechanisms contributing to GLD.
2023-06-13 | CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy
Globoid cell leukodystrophy (GLD) or Krabbe’s disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein, we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD. Administration of a function-blocking antibody against CD8α effectively prevented disease onset, reduced morbidity and mortality, and prevented CNS demyelination in mice. These data indicate that subsequent to the genetic cause of disease, neuropathology is driven by pathogenic CD8+ T cells, thus offering novel therapeutic potential for treatment of GLD.
2022-10-03 | Therapeutic depletion of CD8+ T-cells prevents myelin pathology in Globoid Cell Leukodystrophy
Abstract Globoid cell leukodystrophy (GLD) or Krabbe’s disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD. Administration of a function blocking antibody against CD8α effectively prevented disease onset, reduced morbidity and mortality and prevented CNS demyelination in mice. These data indicate that subsequent to the genetic cause of disease, neuropathology is driven by pathogenic CD8+ T cells, thus offering novel therapeutic potential for treatment of GLD. One-Sentence Summary CD8 T-cells mediate demyelination and neuroinflammation in a genetic white matter disease.
2021-04-16 | Adult Krabbe Disease That Was Successfully Treated with Intravenous Immunoglobulin.
Krabbe disease involves the accumulation of neurotoxic metabolites due to lysosomal galactocerebrosidase enzyme deficiency, which results in widespread demyelination of central and peripheral nerves. Generally, Krabbe disease presents as spastic paraplegia with a slow progressive course; however, some cases may show clinical symptoms similar to those of chronic inflammatory demyelinating polyneuropathy (CIDP). No previously reported studies have investigated the efficacy of intravenous immunoglobulin (IVIg) for treating Krabbe disease, and reporting a case involving IVIg treatment may be informative in the clinical setting. A 14-year-old girl who developed Guillain-Barré syndrome-like limb weakness was administered IVIg, and her limb weakness improved. At 16 years old, she developed abnormal sensory perception and weakness of both upper limbs. A nerve conduction study revealed demyelination, which led us to suspect CIDP. IVIg was administered, and her symptoms gradually improved. A nerve biopsy, enzyme activity, and genetic test results indicated adult Krabbe disease. In some cases, IVIg may be an effective treatment for Krabbe disease.
2006-10-25 | Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice
PLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants with RAG-1-deficient mice lacking mature lymphocytes, we could recently demonstrate a pathogenetic impact of the CD8+ cells. In the present study, we investigated the pathogenetic impact of CD11b+ macrophages by crossbreeding the myelin mutants with knockout mice deficient for the macrophage-restricted adhesion molecule sialoadhesin (Sn). In the wild-type mice, Sn is barely detectable on CD11b+ cells, whereas in the myelin mutants, almost all CD11b+ cells express Sn. In the double mutants, upregulation of CD8+ T-cells and CD11b+ macrophages is reduced and pathological alterations are ameliorated. These data indicate that in a primarily genetically caused myelin disorder of the CNS macrophages expressing Sn partially mediate pathogenesis. These findings may have substantial impact on treatment strategies for leukodystrophic disorders and some forms of multiple sclerosis.
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Drug Discovery Landscape
11 orphan drug designations for Krabbe disease.
11 orphan drug designations for Krabbe disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant serotype 9 adeno-associated virus (AAV) encoding a human galactosylceramidase (GALC) transgene (hGALC) | gene therapies | FDA | 2024-10-29 | — | Elpida Therapeutics SPC |
Recombinant serotype 9 adeno-associated virus encoding a codon-optimized human galactosylceramidase (GALC) transgene (hGALCopt2) | gene therapies | FDA | 2022-02-10 | — | Neurogene Inc. |
Adeno-associated virus serotype rh10 containing the human GALC gene | gene therapies | EMA | 2021-10-15 | — | Forge Biologics Europe S.L. |
Gemfibrozil | small molecules | FDA | 2021-08-30 | — | Polaryx Therapeutics, Inc. |
Adeno-associated virus serotype hu68 containing the human GALC gene | gene therapies | EMA | 2021-03-26 | — | FGK Representative Service GmbH |
adeno-associated virus serotype rhesus 10 vector expressing the human galactocerebrosidase (GALC) gene | gene therapies | FDA | 2021-02-10 | — | Joanne Kurtzberg, MD |
Trans-Cinnamic Acid | gene therapies | FDA | 2021-02-03 | — | Polaryx Therapeutics, Inc. |
a non-replicating recombinant adeno-associated virus serotype hu68 vector, containing a transgene encoding the human galactosylceramidase (GALC) enzyme | gene therapies | FDA | 2020-10-22 | — | GEMMA Biotherapeutics |
ibudilast | small molecules | FDA | 2015-06-01 | — | MediciNova, Inc. |
recombinant human galactocerebrosidase (rhGALC); | proteins | FDA | 2011-12-12 | — | Chiesi USA, Inc. |
RECOMBINANT HUMAN GALACTOCEREBROSIDASE [Galaczym] | proteins | EMA | 2011-09-27 | — | Chiesi Farmaceutici S.p.A. |
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