RARE DISEASE
Niemann-Pick disease type C
Niemann-Pick disease type C
Niemann-Pick disease type C
Drug discovery
22
drugs
With orphan designations
Overview
Niemann-Pick disease type C (NPC) is a rare, autosomal recessive lysosomal storage disorder caused by NPC1 or NPC2 gene mutations, disrupting intracellular cholesterol and lipid transport. This leads to progressive neurovisceral accumulation, resulting in hepatosplenomegaly, vertical supranuclear gaze palsy, cerebellar ataxia, dystonia, cognitive decline, and psychiatric manifestations. Diagnosis spans from infancy to adulthood, with variable progression and fatal neurodegenerative outcomes [1][5][6][13][16].
Therapies
Miglustat: Reduces glycosphingolipid synthesis, slowing neurological progression [1][7][19].
2-hydroxypropyl-β-cyclodextrin (HPβ-CD): Investigational therapy showing extended survival in trials [3][7][19].
Arimoclomol: Recently FDA-approved, enhancing heat shock proteins to mitigate protein misfolding [15][19].
Supportive care (e.g., multidisciplinary symptom management, seizure control) [1][5][9].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare respiratory diseases, rare transplant-related disorders
Research Papers
721 drug discovery papers about Niemann-Pick disease type C, with 5 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
721 drug discovery papers about Niemann-Pick disease type C, with 5 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-08-30 | Menstrual blood-derived endometrial stem cells ameliorate neuroinflammation and apoptosis through JAK2/STAT3 signaling pathway in NPC1 mutant cell and mice.
Niemann-Pick disease type C1 (NPC1) is caused by NPC1 gene mutations, resulting in Purkinje cell degeneration and death, glial cell activation, and progressive neurodegeneration. Menstrual blood-derived endometrial stem cells (MenSCs) have been explored as a promising tool for treating neurodegenerative diseases due to their wide range of sources, non-invasive nature, and regular collection methods. This study aims to investigate whether MenSCs can improve neuroinflammation and apoptosis in NPC1 mutant cell (Npc1KO BV2 cell line) and mice (Npc1-/- mice), and explore their underlying mechanisms. MenSCs were transplanted into the 4-week-old Npc1-/- mice cerebellum through stereotaxic injection, and their effects on weight, behavior, and survival were assessed. The activation of glial cells and the survival of neurons were detected by immunofluorescence technology, and the expression level of related inflammatory factors and apoptotic proteins was detected by western blotting. The transcriptome changes in cerebellum after MenSCs transplantation were analyzed by transcriptome sequencing. The mechanism by which MenSCs treat NPC1 was validated at the cellular level using the activator butyzamide. MenSCs transplantation could slow down the rate of weight loss and improve motor coordination in Npc1-/- mice, but had no significant improvement in lifespan. MenSCs could mitigate the activation of glial cells, alleviate neuroinflammation, reduce cell apoptosis, and increase the number of mature neurons and Purkinje cells in the cerebellum. Transcriptome analyses results indicated that the JAK/STAT signaling pathway changed across different groups. Compared with age-matched Npc1+/+ mice, the protein expression levels of P-JAK2 and P-STAT3, the ratios of P-JAK2/JAK2 and P-STAT3/STAT3 were increased in the cerebellum of 5-week-old Npc1-/- mice in the PBS group; compared with age-matched Npc1-/- mice in the PBS group, the protein expression levels of P-JAK2 and P-STAT3, the ratios of P-JAK2/JAK2 and P-STAT3/STAT3 were decreased after MenSCs transplantation. Finally, treating Npc1KO BV2 cells with butyzamide further confirmed that MenSCs relieve inflammation and apoptosis caused by Npc1 gene mutations through JAK2/STAT3 signaling pathway. Our study demonstrate that MenSCs ameliorate neuroinflammation and apoptosis in NPC1 mutant cell and mice through JAK2/STAT3 signaling pathway.
2023-06-27 | Peripheral immune system modulates Purkinje cell degeneration in Niemann–Pick disease type C1
Niemann–Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM–derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.
2021-03-03 | Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.
Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1-/- microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.
2021-01-07 | Induced neural stem cells from human patient-derived fibroblasts attenuate neurodegeneration in Niemann-Pick type C mice
Background: Niemann-Pick disease type C (NPC) is caused by the mutation of NPC genes, which leads to the abnormal accumulation of unesterified cholesterol and glycolipids in lysosomes.This autosomal recessive disease is characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration.Recently, the application of induced neural stem cells (iNSCs), converted from fibroblasts using specific transcription factors, to repair degenerated lesions has been considered a novel therapy.Objectives: The therapeutic effects on NPC by human iNSCs generated by our research group have not yet been studied in vivo; in this study, we investigate those effects.Methods: We used an NPC mouse model to efficiently evaluate the therapeutic effect of iNSCs, because neurodegeneration progress is rapid in NPC.In addition, application of human iNSCs from NPC patient-derived fibroblasts in an NPC model in vivo can give insight into the clinical usefulness of iNSC treatment.The iNSCs, generated from NPC patientderived fibroblasts using the SOX2 and HMGA2 reprogramming factors, were transplanted by intracerebral injection into NPC mice.Results: Transplantation of iNSCs showed positive results in survival and body weight change in vivo.Additionally, iNSC-treated mice showed improved learning and memory in behavior test results.Furthermore, through magnetic resonance imaging and histopathological assessments, we observed delayed neurodegeneration in NPC mouse brains.Conclusions: iNSCs converted from patient-derived fibroblasts can become another choice of treatment for neurodegenerative diseases such as NPC.
2020-05-29 | Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment.
Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease.
small molecules
2026-09-26 | Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing.
Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood-brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann-Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay-Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.
2026-09-18 | Conformation switch of NPC1 epitomizes a luminal alternating access for nonpolar substrates
Niemann-Pick disease type C (NPC) arises from failure of the NPC1 and/or NPC2 proteins to mobilize lysosomal cholesterol, yet the mechanism by which the complex drives sterol translocation lacks a thorough understanding (1, 2). Here, we capture an NPC1-NPC2 complex conformation at lysosomal pH using a bis-sterol ligand (JM046), fortifying NPC2 engagement with NPC1 and enabling structural characterization of an alternative transport state. In this complex, the sterol moiety is absent from the NPC1 central tunnel, and the neck site adopts an expanded architecture that resembles a previously observed NPC1 conformation at neutral pH, indicating that the tunnel geometry is not influenced by the pH alone. Instead, we provide evidence that cholesterol occupancy in the neck site is a key determinant of tunnel contraction. Supporting this notion, NPC1 purified from cholesterol-auxotrophic insect cells exhibits a similar expanded neck conformation. Integrating these structures and molecular dynamics (MD) simulations exploring the directional cholesterol handoff from NPC2 to the NPC1 tunnel, we propose a substrate-induced gating cycle where luminal and membrane-facing openings of NPC1 switch states in a coordinated manner to transfer cholesterol across the hydrophilic glycocalyx. This mechanism is reminiscent of the alternating access mechanism for hydrophobic substrate transfer. This framework synthesizes NPC1 conformational states into a mechanistic basis to classify pathogenic NPC variants by relevant transport steps, which will illuminate mechanism-guided therapeutic strategies.
2026-08-31 | Pharmacological BET Protein Inhibition Reverts Niemann-Pick Type C Disease-Associated Changes in Human iPSC-Derived Cortical Neurons
Dataset associated with the paper titled "Pharmacological BET Protein Inhibition Reverts Niemann-Pick Type C Disease-Associated Changes in Human iPSC-Derived Cortical Neurons": This set of raw data cannot be made publicly available as including sensitive information, but might be made available to interested researchers upon reasonable requests. Please, forward your request to: claudia.compagnucci@opbg.net.
2026-08-29 | Proteomic Signatures in Neuronal and Glial Cell Models of Niemann-Pick Disease Type C
Abstract Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by the accumulation of unesterified cholesterol and glycosphingolipids in the late endosomal/lysosomal system, resulting in region-specific neurodegeneration. While the mechanism through which defective NPC1 protein and thus altered cholesterol transport engenders neurodegeneration is unknown, selective reintroduction of the NPC1 gene in different cell types in the mouse brain can alleviate disease symptoms, suggesting that neuronal and glial cells may play distinct roles in disease mechanisms. Here, in an in vitro NPC model, we evaluate cell-specific changes in the proteome upon treatment with a small-molecule cholesterol-trafficking inhibitor, U18666A, which inhibits NPC1 function across three immortalized cell lines in the central nervous system (CNS): mouse hippocampal neuronal cells (HT-22), mouse microglial cells (SIM-A9), and human hybridized oligodendrocytes (MO3.13). Using nanoliquid chromatography–mass spectrometry (LC–MS) techniques, we observe 21 common proteins upregulated in all U18666A-treated cells. We also note that markers of activated microglia were significantly altered in SIM-A9 microglial cells, whereas cytoskeletal and membrane-related proteins were elevated in MO3.13. In HT-22 hippocampal neuronal cells, we identify protein changes associated with altered glucose metabolism and postulate that ATP-citrate lyase (ACLY), a protein central to multiple biological pathways, might play a role in responding to aberrant cholesterol trafficking and metabolism in NPC.
2026-08-13 | Disarming cGAS-STING hyperactivation in autoimmune and inflammatory diseases: Pathogenic mechanisms and emerging therapeutic strategies.
Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been increasingly recognized as a key driver of autoimmune and inflammatory diseases. In recent years, accumulating evidence has highlighted the close association between cGAS-STING signaling and the pathogenesis of these disorders, suggesting that pharmacological targeting of this pathway may represent a promising therapeutic strategy. This review provides a comprehensive overview of the molecular mechanisms underlying cGAS-STING hyperactivation and its pathological roles across diverse diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH), STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, Niemann-Pick disease type C (NPC), neurodegenerative diseases and cancer. We critically evaluate current and emerging pharmacological strategies targeting the cGAS-STING pathway, encompassing direct cGAS and STING inhibitors, protein degradation technologies, epigenetic modulation, regulation of biomolecular phase separation, and artificial intelligence (AI)-enabled drug discovery approaches. By integrating disease-specific pathogenic mechanisms with therapeutic opportunities, this review highlights key challenges and future directions in the development of cGAS-STING-targeted therapies. Collectively, these insights provide a translational perspective for precision targeting of pathological cGAS-STING activation.
proteins
2026-05-29 | Npc1 deficiency impairs brain vascular integrity in mouse model of Niemann-Pick disease type C1.
Niemann-Pick disease type C1 is a rare and fatal neurodegenerative disorder caused by mutations in the NPC1 gene. Proper formation and function of vascular system are essential for maintaining homeostasis of the central nervous system. However, the vascular contribution to NPC1 pathogenesis remains largely unexplored. Here, we demonstrate that loss of Npc1, a transmembrane protein involved in intracellular cholesterol trafficking, results in vascular abnormalities in the mouse brain. Npc1-deficient mice exhibit distorted vascular architecture, increased blood-brain barrier (BBB) permeability, and enhanced microglia-endothelial cell contacts. Investigation of molecular perturbations upon endothelial Npc1 deficiency shows impairment of lipid metabolism and compromised Rap1 signaling and tight junctions in endothelial cells. These changes were in part reverted by release of lysosomal cholesterol. Collectively, these results suggest that Npc1 is involved in the regulation of brain vascular integrity and highlight brain endothelial cells as a potential therapeutic target for NPC1 disease.
2025-06-12 | Genomic modifiers of neurological resilience in a Niemann‐Pick C family
Niemann‐Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss‐of‐function variants in CCDC115 , SLC4A5 , DEPDC5 , ETFDH , SNRNP200 , and DOCK1 that co‐segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC‐like severity based on orthologous gene variants. RNA‐seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1 , enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target. Impact statement Niemann‐Pick type C (NPC) disease is a progressive neurovisceral lysosomal storage disorder. Here, we identified genomic modifiers of neurological resilience in an NPC family, with SLC4A5 emerging as a key biomarker and therapeutic target. Additionally, our study highlighted mitochondrial transcripts and metabolites as potential biomarkers of severity.
2025-04-01 | Abstract Tu0018: Development of Nanodiscs with Embedded Acid Sphingomyelinase for Treatment of Niemann-Pick Disease
Lysosomal storage disorders (LSDs) are genetic metabolic diseases with lysosomal enzyme deficiencies. Deficiency of or defective acid sphingomyelinase (ASM) causes Niemann-Pick disease types A and B (NPDA and NPDB, respectively), neurological disorders characterized by accumulation of sphingomyelin. We developed a nanodisc (ND)-based platform wherein recombinant ASM has been embedded in a bilayer of phospholipids circumscribed by apolipoprotein E3 (apoE3) for targeted delivery to the lysosomes. The rationale is that apoE3 would serve as a high-affinity ligand via its N-terminal (NT) domain for the low-density lipoprotein receptors (LDLr) facilitating receptor-mediated endocytosis of the nanodisc; the nanodisc and its components would eventually disintegrate in the low-pH environment of the lysosomes thereby releasing the embedded ASM. We designed a fusion protein comprising the essential catalytic domain of ASM flanked by the transmembrane domain (TMD) of a pulmonary surfactant protein at the N-terminal end and a His-tag at the C-terminal end to facilitate purification. The fusion construct termed TMD-ASM was expressed and purified from a bacterial expression system, and the identity confirmed by Western blot using anti-ASM and anti-His tag antibodies. TMD-ASM was reconstituted with phospholipids and apoE3 NT to promote formation of lipoprotein complexes, followed by density gradient ultracentrifugation to isolate nanodiscs with ASM (TMD-ASM-ND). Empty ND without the embedded ASM were generated in parallel. Physicochemical characterization using SDS-PAGE shows the presence of both ASM (35kDa) and apoE3NT (24 kDa) in the nanodisc preparations, while native PAGE revealed the formation of large complexes (~600 kDa) of ~ 15 nm diameter. Electron microscopy imaging of TMD-ASM-ND revealed nanodisc formation, while atomic force microscopy showed nanodisc ~15 nm high. Co-immunoprecipitation confirmed the presence of ASM in nanodiscs, while sphingomyelinase activity assays revealed robust ASM activity of TMD-ASM-ND. Lastly, glioblastoma cells, which are known to overexpress LDLr were treated with TMD-ASM-ND and the cellular uptake followed by immunofluorescence. Fluorescence microscopy revealed punctate perinuclear vesicles with co-localization of ASM with apoE3 and lysosomal marker, indicative of successful targeting of ASM to the lysosomes. These findings show potential for targeted delivery of ASM using nanodiscs to treat NPD by enzyme replacement therapy.
2024-08-23 | Npc1 deficiency impairs microglia function via TREM2-mTOR signaling in Niemann-Pick disease type C.
Niemann-Pick disease Type C (NPC) is a neurodegenerative disease mainly caused by the mutation in NPC1 gene, leading to massive accumulation of unesterified cholesterol in the late endosome/lysosome of cells. Impaired phenotype of microglia is a hallmark in Npc1 mutant mice (Npc1-/- mice). However, the mechanism of Npc1 in regulating microglial function is still unclear. Here, we showed that the reactive microglia in the neonatal Npc1-/- mice indicated by the increased lysosome protein CD68 and phagocytic activity were associated with disrupted TREM2-mTOR signaling in microglia. Furthermore, in Npc1-deficient BV2 cells, genetic deletion of Trem2 partially restored microglial function, probably via restored mTOR signaling. Taken together, our findings indicated that loss of Npc1 in microglia caused changes of their morphologies and the impairment of lysosomal function, which were linked to the TREM2-mTOR signaling pathway.
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
gene therapies
2026-07-09 | Molecular and Structural Basis of Cardiac Remodelling in Niemann-Pick Type C
Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in NPC1 or NPC2. Sudden death can occur due to seizures, but cardiac involvement has not been well defined. We performed 12-lead electrocardiograms (ECG) in 14 adult NPC patients (8 male, 6 female). Cardiac structure and function were examined in Npc1-/- adult mouse hearts, alongside wild-type controls. Glycosphingolipid accumulation was quantified by high-performance liquid chromatography, fibrosis and collagen deposition were quantified using Massons Trichrome (M&T) and Picrosirius Red (PR) staining. Whole-heart morphology, including chamber size and wall thickness, was assessed. Ex vivo ECG recordings assessed conduction abnormalities and arrhythmias. RNA-seq transcriptomics characterised molecular pathways altered in Npc1-/- hearts. 8/14 patients showed ECG abnormalities including abnormal QRS transitions (N=8), increased QRS amplitude (N=4), fascicular block (N=2), and abnormal T wave inversion (N=1). 13 patients also had transthoracic echocardiograms identifying mildly impaired LV systolic function (N=2) and increased wall thickness/LV mass (N=4). In Npc1-/- mice, age‑related glycosphingolipid accumulation was associated with pronounced ventricular fibrotic remodelling. There was a significant increase in stained connective tissue area and connective tissue to cardiac tissue ratio in both MT and PR staining. ECG from Langendorff-perfused Npc1-/- hearts showed QT prolongation and atrioventricular conduction abnormalities under isoprenaline stress. Transcriptomics revealed major changes in Npc1-/- hearts, consistent with histological fibrosis and linking NPC to inflammation-driven remodelling and arrhythmogenesis. These findings support routine cardiac screening in NPC patients and highlight the need for further studies to improve management and treatment.
2026-06-20 | Facilitate by-stander effects by EV-mRNA cargo in AAV gene replacement therapy for treating NPC-1
Niemann-Pick Disease Type C (NPC) is a rare lysosomal storage disease with an estimated incidence of 1:100,000 to 1:120,000. 95% of NPC cases are caused by autosomal recessive mutations in Intracellular Cholesterol Transporter 1 (NPC1). NPC1 is a transmembrane protein and functions as a trans-lysosomal lipid transporter.1,2 Adeno-associated virus (AAV) gene therapy’s recent success offers a unique opportunity for treating neurogenetic diseases such as NPC that has not been previously explored.3 All cells continuously release extracellular vesicles (EVs) that carry large biological molecules, as intercellular communication mediators. 4 We hypothesize that incorporating EV-mRNA signal in AAV vector expressing NPC1 may facilitate by-stander-effects and enhance the efficacy.5 To test our hypothesis, we constructed pucIDT-hNPC1 plasmids with/without an EV-mRNA packaging ZC signal and tested it in human NPC skin fibroblasts. The hNPC1ZC plasmid increased hNPC1 mRNA expression and mediated the release of EVs-hNPC1-mRNA. Furthermore, human NPC cells excrete significantly more EVs than normal human cells, which were reduced to normal levels after transfection with the pucIDT-hNPC1zc plasmid. These data support our hypothesis that the incorporation of ZC signal in the hNPC1 vector directs packaging of hNPC1-mRNA in EVs. In future studies, we will determine if EV-hNPC1 mRNA can be transported to NPC cells and translated into functional NPC1 protein. We will then clone the hNPC1zc into rAAV-hNPC1zc vector and test the rAAV vector in vivo in NPC mice. This study supports the therapeutic potential of using the EV-mRNA cargo signal in rAAV-hNPC1 vector, allowing optimal benefits for treating NPC with relatively low dose, without having to transduce every individual cell.
2026-05-28 | Essential genetic testing in movement disorders - results from a Delphi study.
While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial. Establish a list of genetic movement disorders considered essential as determined by a group of MD experts. All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic. Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington's disease, PxMD-PPRT2, Wilson's disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C. This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts.
2026-03-31 | Optimization of systemic AAV9 gene therapy in Niemann-Pick disease, type C1 mice.
Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variants in NPC1, which encodes a lysosomal cholesterol transporter. FDA-approved treatments are limited and do not target the underlying genetic defect. Both systemic and central nervous system delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null Npc1 m1N/m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 wk old. Then, to assess the impact of age, we administered the medium dose before phenotypic onset or at early or late stage of disease progression (4, 6, or 8 wk old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced central nervous system transduction. In Npc1 I1061T/I1061T mice, a model recapitulating a common human hypomorphic variant, similar benefits ensued. Our findings help define dose ranges, treatment ages, and efficacy in hypomorphic models of NPC1 deficiency and suggest that higher doses of AAV9-hNPC1 in presymptomatic disease states are likely to yield better outcomes in NPC1 individuals.
2026-03-26 | An Analysis of Biomarkers for the Evaluation of Gene Therapy in Niemann-Pick Disease Type C1 Mice.
Niemann-Pick disease type C1 (NPC1) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants of the NPC1 gene that encodes a protein essential for lysosomal cholesterol transport. A deficiency in NPC1 results in the accumulation of unesterified cholesterol and sphingolipids, leading to neurological, psychiatric, and hepatic manifestations from infancy to adulthood. The currently approved treatment is palliative. Although the efficacy of gene therapy has been demonstrated in murine models, reliable biomarkers for evaluating the treatment effects remain unknown. We evaluated adeno-associated virus (AAV) vector-mediated NPC1 gene therapy in Npc1 homo-knockout (Npc1-/-) mice, focusing on blood-based biomarkers. An AAV vector carrying human NPC1 under a cytomegalovirus promoter (AAV-hNPC1) was administered intraperitoneally on days 6-8 after birth at varying vector doses and analyzed at multiple time points: 1.8 × 1011 vector genomes/mouse analyzed at 7 weeks (Low/7w) and 1.0 × 1012 vector genomes/mouse at 4 weeks (High/4w) and 9 weeks (High/9w). hNPC1 is expressed in the brain and liver, and a degree of neuronal cell survival is observed. High-dose AAV treatment improves body weight and rotarod performance. Plasma N-palmitoyl-O-phosphocholine-serine (PPCS) and lysosphingomyelin (lyso-SM) levels were significantly elevated in Npc1-/- mice. PPCS increased with disease progression but was significantly decreased after later points of high-dose AAV treatment (saline-treated Npc1-/- mice: 12.88 ± 3.53 ng/mL, AAV-treated Npc1-/- mice: 7.87 ± 1.67 ng/mL, p = 0.0008). Lyso-SM and oxysterols showed limited changes after therapy. Vector genome analysis revealed higher and more sustained levels in the brain than in the liver, which is consistent with rapid hepatocyte proliferation-reducing vector persistence. These findings demonstrate that systemic AAV-hNPC1 therapy ameliorates motor and neurological deficits but has a limited impact on several cholesterol-related biomarkers. PPCS has been suggested as a sensitive biomarker of therapeutic response and warrants further evaluations in preclinical and clinical NPC1 gene therapy trials.
other
2026-03-09 | Case Report: Interleukin-23 blockade achieves sustained remission in Niemann-Pick type C-associated Crohn's disease refractory to anti-tumor necrosis factor therapy.
Niemann-Pick type C (NPC) is a lysosomal lipid trafficking disorder that is associated with defective autophagy and impaired bacterial clearance, potentially predisposing patients to Crohn's disease (CD)-like granulomatous enteritis. Tumor necrosis factor-alpha inhibitors are typically the first-line biologic treatment for CD. However, due to limited evidence-based data, the optimal treatment for NPC-associated CD remains unclear. A 20-year-old female patient with genetically confirmed NPC developed diarrhea and refractory perianal abscesses at the age of 17 years. Colonoscopy showed discontinuous longitudinal erosions, and histological examination revealed chronic inflammation with granulomas. Based on these finding, a diagnosis of CD complicating NPC was made. Adalimumab was not successful in maintaining remission despite corticosteroid therapy. Ustekinumab induced steroid-free remission. Nevertheless, its effect diminished before each dosing interval. Switching to risankizumab achieved stable remission, which was maintained for 3 years. During interleukin (IL)-23 blockade therapy, the patient developed an infection associated with an intrathecal baclofen pump. This case indicates that IL-12/23 and IL-23 inhibitors can be effective therapeutic options for NPC-associated CD. Furthermore, it supports the hypothesis that IL-23-driven inflammation plays a role in the development of this condition. These findings should be considered hypothesis-generating and validated in additional cases.
2025-01-07 | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression.
Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl4 induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport. We identify that the 692-854 amino acid region of NPC1's transmembrane domain is critical for its interaction with TGF-β receptor type-1 (TGFBR1). This interaction prevents the binding of SMAD7 and SMAD ubiquitylation regulatory factors (SMURFs) to TGFBR1, reducing TGFBR1 ubiquitylation and degradation, thus enhancing its stability. Notably, the NPC1 (P691S) mutant, which is defective in cholesterol transport, still binds TGFBR1, underscoring a cholesterol-independent mechanism. These findings highlight a cholesterol transport-independent mechanism by which NPC1 contributes to the stability of TGFBR1 in HCC and suggest potential therapeutic strategies targeting NPC1 for HCC treatment.
2023-10-14 | Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders
Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.
2022-03-31 | The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C.
Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages, are particularly vulnerable to lysosome dysfunction because of the phagocytic stress of clearing dying neurons, myelin, and debris. CD22 is a negative regulator of microglial homeostasis in the aging mouse brain, and soluble CD22 (sCD22) is increased in the cerebrospinal fluid of patients with Niemann-Pick type C disease (NPC). However, the role of CD22 in the human brain remains unknown. In contrast to previous findings in mice, here, we show that CD22 is expressed by oligodendrocytes in the human brain and binds to sialic acid–dependent ligands on microglia. Using unbiased genetic and proteomic screens, we identify insulin-like growth factor 2 receptor (IGF2R) as the binding partner of sCD22 on human myeloid cells. Targeted truncation of IGF2R revealed that sCD22 docks near critical mannose 6-phosphate–binding domains, where it disrupts lysosomal protein trafficking. Interfering with the sCD22-IGF2R interaction using CD22 blocking antibodies ameliorated lysosome dysfunction in human NPC1 mutant induced pluripotent stem cell–derived microglia-like cells without harming oligodendrocytes in vitro. These findings reinforce the differences between mouse and human microglia and provide a candidate microglia-directed immunotherapeutic to treat NPC.
2022-03-24 | Cerebellar Long Noncoding RNA Expression Profile in a Niemann-Pick C Disease Mouse Model.
Niemann-Pick type C (NP-C) disease is a neurodegenerative lysosomal storage disorder primarily caused by mutations in NPC1. However, its pathogenesis remains poorly understood. While mounting evidence has demonstrated the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of neurodegenerative disorders, the lncRNA expression profile in NP-C has not been determined. Here, we used RNA-seq analysis to determine lncRNA and mRNA expression profiles of the cerebella of NPC1-/- mice. We found that 272 lncRNAs and 856 mRNAs were significantly dysregulated in NPC1-/- mice relative to controls (≥ 2.0-fold, p < 0.05). Quantitative real-time PCR (qRT-PCR) was utilized to validate the expression of selected lncRNAs and mRNAs. Next, a lncRNA-mRNA coexpression network was employed to examine the potential roles of the differentially expressed (DE) lncRNAs. Functional analysis revealed that mRNAs coexpressed with lncRNAs are mainly linked to immune system-related processes and neuroinflammation. Moreover, knockdown of the lncRNA H19 ameliorated changes in ROS levels and cell viability and suppressed the lipopolysaccharide (LPS)-induced inflammatory response in vitro. Our findings indicate that dysregulated lncRNA expression patterns are associated with NP-C pathogenesis and offer insight into the development of novel therapeutics based on lncRNAs.
cell therapies
2025-08-30 | Menstrual blood-derived endometrial stem cells ameliorate neuroinflammation and apoptosis through JAK2/STAT3 signaling pathway in NPC1 mutant cell and mice.
Niemann-Pick disease type C1 (NPC1) is caused by NPC1 gene mutations, resulting in Purkinje cell degeneration and death, glial cell activation, and progressive neurodegeneration. Menstrual blood-derived endometrial stem cells (MenSCs) have been explored as a promising tool for treating neurodegenerative diseases due to their wide range of sources, non-invasive nature, and regular collection methods. This study aims to investigate whether MenSCs can improve neuroinflammation and apoptosis in NPC1 mutant cell (Npc1KO BV2 cell line) and mice (Npc1-/- mice), and explore their underlying mechanisms. MenSCs were transplanted into the 4-week-old Npc1-/- mice cerebellum through stereotaxic injection, and their effects on weight, behavior, and survival were assessed. The activation of glial cells and the survival of neurons were detected by immunofluorescence technology, and the expression level of related inflammatory factors and apoptotic proteins was detected by western blotting. The transcriptome changes in cerebellum after MenSCs transplantation were analyzed by transcriptome sequencing. The mechanism by which MenSCs treat NPC1 was validated at the cellular level using the activator butyzamide. MenSCs transplantation could slow down the rate of weight loss and improve motor coordination in Npc1-/- mice, but had no significant improvement in lifespan. MenSCs could mitigate the activation of glial cells, alleviate neuroinflammation, reduce cell apoptosis, and increase the number of mature neurons and Purkinje cells in the cerebellum. Transcriptome analyses results indicated that the JAK/STAT signaling pathway changed across different groups. Compared with age-matched Npc1+/+ mice, the protein expression levels of P-JAK2 and P-STAT3, the ratios of P-JAK2/JAK2 and P-STAT3/STAT3 were increased in the cerebellum of 5-week-old Npc1-/- mice in the PBS group; compared with age-matched Npc1-/- mice in the PBS group, the protein expression levels of P-JAK2 and P-STAT3, the ratios of P-JAK2/JAK2 and P-STAT3/STAT3 were decreased after MenSCs transplantation. Finally, treating Npc1KO BV2 cells with butyzamide further confirmed that MenSCs relieve inflammation and apoptosis caused by Npc1 gene mutations through JAK2/STAT3 signaling pathway. Our study demonstrate that MenSCs ameliorate neuroinflammation and apoptosis in NPC1 mutant cell and mice through JAK2/STAT3 signaling pathway.
2023-06-27 | Peripheral immune system modulates Purkinje cell degeneration in Niemann–Pick disease type C1
Niemann–Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM–derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.
2021-03-03 | Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.
Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1-/- microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.
2021-01-07 | Induced neural stem cells from human patient-derived fibroblasts attenuate neurodegeneration in Niemann-Pick type C mice
Background: Niemann-Pick disease type C (NPC) is caused by the mutation of NPC genes, which leads to the abnormal accumulation of unesterified cholesterol and glycolipids in lysosomes.This autosomal recessive disease is characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration.Recently, the application of induced neural stem cells (iNSCs), converted from fibroblasts using specific transcription factors, to repair degenerated lesions has been considered a novel therapy.Objectives: The therapeutic effects on NPC by human iNSCs generated by our research group have not yet been studied in vivo; in this study, we investigate those effects.Methods: We used an NPC mouse model to efficiently evaluate the therapeutic effect of iNSCs, because neurodegeneration progress is rapid in NPC.In addition, application of human iNSCs from NPC patient-derived fibroblasts in an NPC model in vivo can give insight into the clinical usefulness of iNSC treatment.The iNSCs, generated from NPC patientderived fibroblasts using the SOX2 and HMGA2 reprogramming factors, were transplanted by intracerebral injection into NPC mice.Results: Transplantation of iNSCs showed positive results in survival and body weight change in vivo.Additionally, iNSC-treated mice showed improved learning and memory in behavior test results.Furthermore, through magnetic resonance imaging and histopathological assessments, we observed delayed neurodegeneration in NPC mouse brains.Conclusions: iNSCs converted from patient-derived fibroblasts can become another choice of treatment for neurodegenerative diseases such as NPC.
2020-05-29 | Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment.
Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease.
small molecules
2026-09-26 | Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing.
Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood-brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann-Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay-Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.
2026-09-18 | Conformation switch of NPC1 epitomizes a luminal alternating access for nonpolar substrates
Niemann-Pick disease type C (NPC) arises from failure of the NPC1 and/or NPC2 proteins to mobilize lysosomal cholesterol, yet the mechanism by which the complex drives sterol translocation lacks a thorough understanding (1, 2). Here, we capture an NPC1-NPC2 complex conformation at lysosomal pH using a bis-sterol ligand (JM046), fortifying NPC2 engagement with NPC1 and enabling structural characterization of an alternative transport state. In this complex, the sterol moiety is absent from the NPC1 central tunnel, and the neck site adopts an expanded architecture that resembles a previously observed NPC1 conformation at neutral pH, indicating that the tunnel geometry is not influenced by the pH alone. Instead, we provide evidence that cholesterol occupancy in the neck site is a key determinant of tunnel contraction. Supporting this notion, NPC1 purified from cholesterol-auxotrophic insect cells exhibits a similar expanded neck conformation. Integrating these structures and molecular dynamics (MD) simulations exploring the directional cholesterol handoff from NPC2 to the NPC1 tunnel, we propose a substrate-induced gating cycle where luminal and membrane-facing openings of NPC1 switch states in a coordinated manner to transfer cholesterol across the hydrophilic glycocalyx. This mechanism is reminiscent of the alternating access mechanism for hydrophobic substrate transfer. This framework synthesizes NPC1 conformational states into a mechanistic basis to classify pathogenic NPC variants by relevant transport steps, which will illuminate mechanism-guided therapeutic strategies.
2026-08-31 | Pharmacological BET Protein Inhibition Reverts Niemann-Pick Type C Disease-Associated Changes in Human iPSC-Derived Cortical Neurons
Dataset associated with the paper titled "Pharmacological BET Protein Inhibition Reverts Niemann-Pick Type C Disease-Associated Changes in Human iPSC-Derived Cortical Neurons": This set of raw data cannot be made publicly available as including sensitive information, but might be made available to interested researchers upon reasonable requests. Please, forward your request to: claudia.compagnucci@opbg.net.
2026-08-29 | Proteomic Signatures in Neuronal and Glial Cell Models of Niemann-Pick Disease Type C
Abstract Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by the accumulation of unesterified cholesterol and glycosphingolipids in the late endosomal/lysosomal system, resulting in region-specific neurodegeneration. While the mechanism through which defective NPC1 protein and thus altered cholesterol transport engenders neurodegeneration is unknown, selective reintroduction of the NPC1 gene in different cell types in the mouse brain can alleviate disease symptoms, suggesting that neuronal and glial cells may play distinct roles in disease mechanisms. Here, in an in vitro NPC model, we evaluate cell-specific changes in the proteome upon treatment with a small-molecule cholesterol-trafficking inhibitor, U18666A, which inhibits NPC1 function across three immortalized cell lines in the central nervous system (CNS): mouse hippocampal neuronal cells (HT-22), mouse microglial cells (SIM-A9), and human hybridized oligodendrocytes (MO3.13). Using nanoliquid chromatography–mass spectrometry (LC–MS) techniques, we observe 21 common proteins upregulated in all U18666A-treated cells. We also note that markers of activated microglia were significantly altered in SIM-A9 microglial cells, whereas cytoskeletal and membrane-related proteins were elevated in MO3.13. In HT-22 hippocampal neuronal cells, we identify protein changes associated with altered glucose metabolism and postulate that ATP-citrate lyase (ACLY), a protein central to multiple biological pathways, might play a role in responding to aberrant cholesterol trafficking and metabolism in NPC.
2026-08-13 | Disarming cGAS-STING hyperactivation in autoimmune and inflammatory diseases: Pathogenic mechanisms and emerging therapeutic strategies.
Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been increasingly recognized as a key driver of autoimmune and inflammatory diseases. In recent years, accumulating evidence has highlighted the close association between cGAS-STING signaling and the pathogenesis of these disorders, suggesting that pharmacological targeting of this pathway may represent a promising therapeutic strategy. This review provides a comprehensive overview of the molecular mechanisms underlying cGAS-STING hyperactivation and its pathological roles across diverse diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH), STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, Niemann-Pick disease type C (NPC), neurodegenerative diseases and cancer. We critically evaluate current and emerging pharmacological strategies targeting the cGAS-STING pathway, encompassing direct cGAS and STING inhibitors, protein degradation technologies, epigenetic modulation, regulation of biomolecular phase separation, and artificial intelligence (AI)-enabled drug discovery approaches. By integrating disease-specific pathogenic mechanisms with therapeutic opportunities, this review highlights key challenges and future directions in the development of cGAS-STING-targeted therapies. Collectively, these insights provide a translational perspective for precision targeting of pathological cGAS-STING activation.
proteins
2026-05-29 | Npc1 deficiency impairs brain vascular integrity in mouse model of Niemann-Pick disease type C1.
Niemann-Pick disease type C1 is a rare and fatal neurodegenerative disorder caused by mutations in the NPC1 gene. Proper formation and function of vascular system are essential for maintaining homeostasis of the central nervous system. However, the vascular contribution to NPC1 pathogenesis remains largely unexplored. Here, we demonstrate that loss of Npc1, a transmembrane protein involved in intracellular cholesterol trafficking, results in vascular abnormalities in the mouse brain. Npc1-deficient mice exhibit distorted vascular architecture, increased blood-brain barrier (BBB) permeability, and enhanced microglia-endothelial cell contacts. Investigation of molecular perturbations upon endothelial Npc1 deficiency shows impairment of lipid metabolism and compromised Rap1 signaling and tight junctions in endothelial cells. These changes were in part reverted by release of lysosomal cholesterol. Collectively, these results suggest that Npc1 is involved in the regulation of brain vascular integrity and highlight brain endothelial cells as a potential therapeutic target for NPC1 disease.
2025-06-12 | Genomic modifiers of neurological resilience in a Niemann‐Pick C family
Niemann‐Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss‐of‐function variants in CCDC115 , SLC4A5 , DEPDC5 , ETFDH , SNRNP200 , and DOCK1 that co‐segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC‐like severity based on orthologous gene variants. RNA‐seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1 , enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target. Impact statement Niemann‐Pick type C (NPC) disease is a progressive neurovisceral lysosomal storage disorder. Here, we identified genomic modifiers of neurological resilience in an NPC family, with SLC4A5 emerging as a key biomarker and therapeutic target. Additionally, our study highlighted mitochondrial transcripts and metabolites as potential biomarkers of severity.
2025-04-01 | Abstract Tu0018: Development of Nanodiscs with Embedded Acid Sphingomyelinase for Treatment of Niemann-Pick Disease
Lysosomal storage disorders (LSDs) are genetic metabolic diseases with lysosomal enzyme deficiencies. Deficiency of or defective acid sphingomyelinase (ASM) causes Niemann-Pick disease types A and B (NPDA and NPDB, respectively), neurological disorders characterized by accumulation of sphingomyelin. We developed a nanodisc (ND)-based platform wherein recombinant ASM has been embedded in a bilayer of phospholipids circumscribed by apolipoprotein E3 (apoE3) for targeted delivery to the lysosomes. The rationale is that apoE3 would serve as a high-affinity ligand via its N-terminal (NT) domain for the low-density lipoprotein receptors (LDLr) facilitating receptor-mediated endocytosis of the nanodisc; the nanodisc and its components would eventually disintegrate in the low-pH environment of the lysosomes thereby releasing the embedded ASM. We designed a fusion protein comprising the essential catalytic domain of ASM flanked by the transmembrane domain (TMD) of a pulmonary surfactant protein at the N-terminal end and a His-tag at the C-terminal end to facilitate purification. The fusion construct termed TMD-ASM was expressed and purified from a bacterial expression system, and the identity confirmed by Western blot using anti-ASM and anti-His tag antibodies. TMD-ASM was reconstituted with phospholipids and apoE3 NT to promote formation of lipoprotein complexes, followed by density gradient ultracentrifugation to isolate nanodiscs with ASM (TMD-ASM-ND). Empty ND without the embedded ASM were generated in parallel. Physicochemical characterization using SDS-PAGE shows the presence of both ASM (35kDa) and apoE3NT (24 kDa) in the nanodisc preparations, while native PAGE revealed the formation of large complexes (~600 kDa) of ~ 15 nm diameter. Electron microscopy imaging of TMD-ASM-ND revealed nanodisc formation, while atomic force microscopy showed nanodisc ~15 nm high. Co-immunoprecipitation confirmed the presence of ASM in nanodiscs, while sphingomyelinase activity assays revealed robust ASM activity of TMD-ASM-ND. Lastly, glioblastoma cells, which are known to overexpress LDLr were treated with TMD-ASM-ND and the cellular uptake followed by immunofluorescence. Fluorescence microscopy revealed punctate perinuclear vesicles with co-localization of ASM with apoE3 and lysosomal marker, indicative of successful targeting of ASM to the lysosomes. These findings show potential for targeted delivery of ASM using nanodiscs to treat NPD by enzyme replacement therapy.
2024-08-23 | Npc1 deficiency impairs microglia function via TREM2-mTOR signaling in Niemann-Pick disease type C.
Niemann-Pick disease Type C (NPC) is a neurodegenerative disease mainly caused by the mutation in NPC1 gene, leading to massive accumulation of unesterified cholesterol in the late endosome/lysosome of cells. Impaired phenotype of microglia is a hallmark in Npc1 mutant mice (Npc1-/- mice). However, the mechanism of Npc1 in regulating microglial function is still unclear. Here, we showed that the reactive microglia in the neonatal Npc1-/- mice indicated by the increased lysosome protein CD68 and phagocytic activity were associated with disrupted TREM2-mTOR signaling in microglia. Furthermore, in Npc1-deficient BV2 cells, genetic deletion of Trem2 partially restored microglial function, probably via restored mTOR signaling. Taken together, our findings indicated that loss of Npc1 in microglia caused changes of their morphologies and the impairment of lysosomal function, which were linked to the TREM2-mTOR signaling pathway.
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
gene therapies
2026-07-09 | Molecular and Structural Basis of Cardiac Remodelling in Niemann-Pick Type C
Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in NPC1 or NPC2. Sudden death can occur due to seizures, but cardiac involvement has not been well defined. We performed 12-lead electrocardiograms (ECG) in 14 adult NPC patients (8 male, 6 female). Cardiac structure and function were examined in Npc1-/- adult mouse hearts, alongside wild-type controls. Glycosphingolipid accumulation was quantified by high-performance liquid chromatography, fibrosis and collagen deposition were quantified using Massons Trichrome (M&T) and Picrosirius Red (PR) staining. Whole-heart morphology, including chamber size and wall thickness, was assessed. Ex vivo ECG recordings assessed conduction abnormalities and arrhythmias. RNA-seq transcriptomics characterised molecular pathways altered in Npc1-/- hearts. 8/14 patients showed ECG abnormalities including abnormal QRS transitions (N=8), increased QRS amplitude (N=4), fascicular block (N=2), and abnormal T wave inversion (N=1). 13 patients also had transthoracic echocardiograms identifying mildly impaired LV systolic function (N=2) and increased wall thickness/LV mass (N=4). In Npc1-/- mice, age‑related glycosphingolipid accumulation was associated with pronounced ventricular fibrotic remodelling. There was a significant increase in stained connective tissue area and connective tissue to cardiac tissue ratio in both MT and PR staining. ECG from Langendorff-perfused Npc1-/- hearts showed QT prolongation and atrioventricular conduction abnormalities under isoprenaline stress. Transcriptomics revealed major changes in Npc1-/- hearts, consistent with histological fibrosis and linking NPC to inflammation-driven remodelling and arrhythmogenesis. These findings support routine cardiac screening in NPC patients and highlight the need for further studies to improve management and treatment.
2026-06-20 | Facilitate by-stander effects by EV-mRNA cargo in AAV gene replacement therapy for treating NPC-1
Niemann-Pick Disease Type C (NPC) is a rare lysosomal storage disease with an estimated incidence of 1:100,000 to 1:120,000. 95% of NPC cases are caused by autosomal recessive mutations in Intracellular Cholesterol Transporter 1 (NPC1). NPC1 is a transmembrane protein and functions as a trans-lysosomal lipid transporter.1,2 Adeno-associated virus (AAV) gene therapy’s recent success offers a unique opportunity for treating neurogenetic diseases such as NPC that has not been previously explored.3 All cells continuously release extracellular vesicles (EVs) that carry large biological molecules, as intercellular communication mediators. 4 We hypothesize that incorporating EV-mRNA signal in AAV vector expressing NPC1 may facilitate by-stander-effects and enhance the efficacy.5 To test our hypothesis, we constructed pucIDT-hNPC1 plasmids with/without an EV-mRNA packaging ZC signal and tested it in human NPC skin fibroblasts. The hNPC1ZC plasmid increased hNPC1 mRNA expression and mediated the release of EVs-hNPC1-mRNA. Furthermore, human NPC cells excrete significantly more EVs than normal human cells, which were reduced to normal levels after transfection with the pucIDT-hNPC1zc plasmid. These data support our hypothesis that the incorporation of ZC signal in the hNPC1 vector directs packaging of hNPC1-mRNA in EVs. In future studies, we will determine if EV-hNPC1 mRNA can be transported to NPC cells and translated into functional NPC1 protein. We will then clone the hNPC1zc into rAAV-hNPC1zc vector and test the rAAV vector in vivo in NPC mice. This study supports the therapeutic potential of using the EV-mRNA cargo signal in rAAV-hNPC1 vector, allowing optimal benefits for treating NPC with relatively low dose, without having to transduce every individual cell.
2026-05-28 | Essential genetic testing in movement disorders - results from a Delphi study.
While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial. Establish a list of genetic movement disorders considered essential as determined by a group of MD experts. All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic. Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington's disease, PxMD-PPRT2, Wilson's disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C. This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts.
2026-03-31 | Optimization of systemic AAV9 gene therapy in Niemann-Pick disease, type C1 mice.
Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variants in NPC1, which encodes a lysosomal cholesterol transporter. FDA-approved treatments are limited and do not target the underlying genetic defect. Both systemic and central nervous system delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null Npc1 m1N/m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 wk old. Then, to assess the impact of age, we administered the medium dose before phenotypic onset or at early or late stage of disease progression (4, 6, or 8 wk old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced central nervous system transduction. In Npc1 I1061T/I1061T mice, a model recapitulating a common human hypomorphic variant, similar benefits ensued. Our findings help define dose ranges, treatment ages, and efficacy in hypomorphic models of NPC1 deficiency and suggest that higher doses of AAV9-hNPC1 in presymptomatic disease states are likely to yield better outcomes in NPC1 individuals.
2026-03-26 | An Analysis of Biomarkers for the Evaluation of Gene Therapy in Niemann-Pick Disease Type C1 Mice.
Niemann-Pick disease type C1 (NPC1) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants of the NPC1 gene that encodes a protein essential for lysosomal cholesterol transport. A deficiency in NPC1 results in the accumulation of unesterified cholesterol and sphingolipids, leading to neurological, psychiatric, and hepatic manifestations from infancy to adulthood. The currently approved treatment is palliative. Although the efficacy of gene therapy has been demonstrated in murine models, reliable biomarkers for evaluating the treatment effects remain unknown. We evaluated adeno-associated virus (AAV) vector-mediated NPC1 gene therapy in Npc1 homo-knockout (Npc1-/-) mice, focusing on blood-based biomarkers. An AAV vector carrying human NPC1 under a cytomegalovirus promoter (AAV-hNPC1) was administered intraperitoneally on days 6-8 after birth at varying vector doses and analyzed at multiple time points: 1.8 × 1011 vector genomes/mouse analyzed at 7 weeks (Low/7w) and 1.0 × 1012 vector genomes/mouse at 4 weeks (High/4w) and 9 weeks (High/9w). hNPC1 is expressed in the brain and liver, and a degree of neuronal cell survival is observed. High-dose AAV treatment improves body weight and rotarod performance. Plasma N-palmitoyl-O-phosphocholine-serine (PPCS) and lysosphingomyelin (lyso-SM) levels were significantly elevated in Npc1-/- mice. PPCS increased with disease progression but was significantly decreased after later points of high-dose AAV treatment (saline-treated Npc1-/- mice: 12.88 ± 3.53 ng/mL, AAV-treated Npc1-/- mice: 7.87 ± 1.67 ng/mL, p = 0.0008). Lyso-SM and oxysterols showed limited changes after therapy. Vector genome analysis revealed higher and more sustained levels in the brain than in the liver, which is consistent with rapid hepatocyte proliferation-reducing vector persistence. These findings demonstrate that systemic AAV-hNPC1 therapy ameliorates motor and neurological deficits but has a limited impact on several cholesterol-related biomarkers. PPCS has been suggested as a sensitive biomarker of therapeutic response and warrants further evaluations in preclinical and clinical NPC1 gene therapy trials.
other
2026-03-09 | Case Report: Interleukin-23 blockade achieves sustained remission in Niemann-Pick type C-associated Crohn's disease refractory to anti-tumor necrosis factor therapy.
Niemann-Pick type C (NPC) is a lysosomal lipid trafficking disorder that is associated with defective autophagy and impaired bacterial clearance, potentially predisposing patients to Crohn's disease (CD)-like granulomatous enteritis. Tumor necrosis factor-alpha inhibitors are typically the first-line biologic treatment for CD. However, due to limited evidence-based data, the optimal treatment for NPC-associated CD remains unclear. A 20-year-old female patient with genetically confirmed NPC developed diarrhea and refractory perianal abscesses at the age of 17 years. Colonoscopy showed discontinuous longitudinal erosions, and histological examination revealed chronic inflammation with granulomas. Based on these finding, a diagnosis of CD complicating NPC was made. Adalimumab was not successful in maintaining remission despite corticosteroid therapy. Ustekinumab induced steroid-free remission. Nevertheless, its effect diminished before each dosing interval. Switching to risankizumab achieved stable remission, which was maintained for 3 years. During interleukin (IL)-23 blockade therapy, the patient developed an infection associated with an intrathecal baclofen pump. This case indicates that IL-12/23 and IL-23 inhibitors can be effective therapeutic options for NPC-associated CD. Furthermore, it supports the hypothesis that IL-23-driven inflammation plays a role in the development of this condition. These findings should be considered hypothesis-generating and validated in additional cases.
2025-01-07 | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression.
Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl4 induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport. We identify that the 692-854 amino acid region of NPC1's transmembrane domain is critical for its interaction with TGF-β receptor type-1 (TGFBR1). This interaction prevents the binding of SMAD7 and SMAD ubiquitylation regulatory factors (SMURFs) to TGFBR1, reducing TGFBR1 ubiquitylation and degradation, thus enhancing its stability. Notably, the NPC1 (P691S) mutant, which is defective in cholesterol transport, still binds TGFBR1, underscoring a cholesterol-independent mechanism. These findings highlight a cholesterol transport-independent mechanism by which NPC1 contributes to the stability of TGFBR1 in HCC and suggest potential therapeutic strategies targeting NPC1 for HCC treatment.
2023-10-14 | Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders
Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.
2022-03-31 | The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C.
Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages, are particularly vulnerable to lysosome dysfunction because of the phagocytic stress of clearing dying neurons, myelin, and debris. CD22 is a negative regulator of microglial homeostasis in the aging mouse brain, and soluble CD22 (sCD22) is increased in the cerebrospinal fluid of patients with Niemann-Pick type C disease (NPC). However, the role of CD22 in the human brain remains unknown. In contrast to previous findings in mice, here, we show that CD22 is expressed by oligodendrocytes in the human brain and binds to sialic acid–dependent ligands on microglia. Using unbiased genetic and proteomic screens, we identify insulin-like growth factor 2 receptor (IGF2R) as the binding partner of sCD22 on human myeloid cells. Targeted truncation of IGF2R revealed that sCD22 docks near critical mannose 6-phosphate–binding domains, where it disrupts lysosomal protein trafficking. Interfering with the sCD22-IGF2R interaction using CD22 blocking antibodies ameliorated lysosome dysfunction in human NPC1 mutant induced pluripotent stem cell–derived microglia-like cells without harming oligodendrocytes in vitro. These findings reinforce the differences between mouse and human microglia and provide a candidate microglia-directed immunotherapeutic to treat NPC.
2022-03-24 | Cerebellar Long Noncoding RNA Expression Profile in a Niemann-Pick C Disease Mouse Model.
Niemann-Pick type C (NP-C) disease is a neurodegenerative lysosomal storage disorder primarily caused by mutations in NPC1. However, its pathogenesis remains poorly understood. While mounting evidence has demonstrated the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of neurodegenerative disorders, the lncRNA expression profile in NP-C has not been determined. Here, we used RNA-seq analysis to determine lncRNA and mRNA expression profiles of the cerebella of NPC1-/- mice. We found that 272 lncRNAs and 856 mRNAs were significantly dysregulated in NPC1-/- mice relative to controls (≥ 2.0-fold, p < 0.05). Quantitative real-time PCR (qRT-PCR) was utilized to validate the expression of selected lncRNAs and mRNAs. Next, a lncRNA-mRNA coexpression network was employed to examine the potential roles of the differentially expressed (DE) lncRNAs. Functional analysis revealed that mRNAs coexpressed with lncRNAs are mainly linked to immune system-related processes and neuroinflammation. Moreover, knockdown of the lncRNA H19 ameliorated changes in ROS levels and cell viability and suppressed the lipopolysaccharide (LPS)-induced inflammatory response in vitro. Our findings indicate that dysregulated lncRNA expression patterns are associated with NP-C pathogenesis and offer insight into the development of novel therapeutics based on lncRNAs.
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Drug Discovery Landscape
22 orphan drug designations for Niemann-Pick disease type C, including 4 approved therapies.
22 orphan drug designations for Niemann-Pick disease type C, including 4 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
cholesteryl oleate | other | FDA | — | Meizon Innovation Pty Ltd. |
AAV9-hNPC1 is an Adeno-Associated Virus 9 (AAV9) vector expressing a human cDNA encoding Niemann-Pick C1 (NPC1), under control of the Elongation Factor 1 alpha Short (EF1S) promoter | gene therapies | FDA | — | National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) |
Adeno-associated viral vector serotype 9 containing the human NPC1 gene | gene therapies | EMA | — | UCL Research Limited |
Adeno-associated viral vector serotype 9 containing the human NPC1 gene | gene therapies | FDA | — | Bloomsbury Genetic Therapies Ltd. |
biphenyl-substituted L-ido configured deoxynojirimycin derivative | small molecules | FDA | Azafaros BV | |
levacetylleucine [Aqneursa] | small molecules | FDA | Approved | IntraBio Inc. |
Miglustat | small molecules | FDA | Edenbridge Pharmaceuticals LLC | |
Ursodeoxycholic acid | small molecules | FDA | — | IntraBio Inc. |
N-acetyl-DL-leucine | small molecules | FDA | IntraBio Inc. | |
Ursodeoxycholic acid | small molecules | EMA | — | IntraBio Ireland Ltd |
Acetylleucine [Aqneursa] | small molecules | EMA | Approved | IntraBio Ireland Ltd |
arimoclomol [Miplyffa] | small molecules | FDA | Approved | Zevra Denmark A/S |
Arimoclomol citrate | small molecules | EMA | Zevra Denmark A/S | |
allopregnanolone | small molecules | FDA | — | La Jolla Pharmaceutical Company, Inc. |
2-hydroxypropyl-ß-cyclodextrin | small molecules | EMA | Eliquent Life Sciences Limited | |
Escherichia coli heat-shock protein 70 | proteins | EMA | — | Orphazyme A/S |
2-hydroxypropyl-B-cyclodextrin | small molecules | FDA | Mandos LLC | |
Hydroxy-propyl-beta-cyclodextrin | small molecules | EMA | Boyd Consultants Limited | |
Hydroxy-Propyl-Beta-Cyclodextrin | small molecules | FDA | Cyclo Therapeutics, Inc. | |
miglustat | small molecules | FDA | Actelion Pharmaceuticals Ltd | |
Miglustat [Zavesca] | small molecules | EMA | [INACTIVE] Actelion Registration Limited | |
Recombinant human acid sphingomyelinase [Xenpozyme] | proteins | EMA | Approved | Sanofi B.V. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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