RARE DISEASE
Alpha-mannosidosis
Alpha-mannosidosis
Alpha-mannosidosis
Synonyms: Lysosomal alpha-D-mannosidase deficiency
Synonyms: Lysosomal alpha-D-mannosidase deficiency
Synonyms: Lysosomal alpha-D-mannosidase deficiency
Drug discovery
4
drugs
With orphan designations
Overview
Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by MAN2B1 gene mutations, leading to deficient alpha-mannosidase enzyme activity. This results in toxic accumulation of mannose-rich oligosaccharides, causing multisystem manifestations such as intellectual disability, hearing loss, skeletal abnormalities, recurrent infections, and psychiatric symptoms. Disease severity ranges from mild (delayed onset) to severe (infantile forms with early mortality). Management focuses on symptom alleviation, enzyme replacement therapy (ERT), and hematopoietic stem cell transplantation (HSCT) in select cases [1][3][9][20].
Burden
Progressive disability: Mobility loss, cognitive decline, and skeletal deformities impair independence [4][5][17].
High caregiver strain: Up to 24 hours/day care required for severe cases, impacting employment and mental health [4][12].
Economic impact: Frequent hospitalizations, specialized care, and therapies contribute to lifelong healthcare costs [4][5][12].
Therapies
Enzyme replacement therapy: Weekly intravenous velmanase alfa (Lamzede®) improves non-neurological symptoms (e.g., mobility, respiratory function) [3][13][17].
HSCT: Stabilizes neurocognitive decline in early-stage patients but carries significant risks [13][18].
Supportive care: Includes antibiotics for infections, hearing aids, physical therapy, and psychiatric support [4][16][18].
Categories: rare bone diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
126 drug discovery papers about Alpha-mannosidosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
126 drug discovery papers about Alpha-mannosidosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-03-20 | Molecular basis of neurocognitive dysfunction and psychosis in Alpha-Mannosidosis
A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines, proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the improvement of neurocognitive symptoms in affected AM individuals.
2023-10-06 | A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency.
A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. A whole genome sequence generated with DNA from the affected dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis. In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. Thus, it appears that storage body autofluorescence and subunit c accumulation are not unique to the NCLs. Consistent with generalized lysosomal impairment, the affected dog exhibited accumulations of intracellular inclusions with varied and complex ultrastructural features characteristic of autophagolysosomes. Impaired autophagic flux may be a general feature of this class of disorders that contributes to disease pathology and could be a target for therapeutic intervention. In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband.
2021-04-15 | Manno-epi-cyclophellitols Enable Activity-Based Protein Profiling of Human α-Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors.
Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce α-mannosidosis-like symptoms. Despite many structural and mechanistic studies of GMII, we still lack a potent and selective inhibitor of this enzyme. Here, we synthesized manno-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of α-mannosidases from both human cell lysate and mouse tissue extracts. Synthesized probes also facilitated a fluorescence polarization-based screen for dGMII inhibitors. We identified seven previously unknown inhibitors of GMII from a library of over 350 iminosugars and investigated their binding modalities through X-ray crystallography. Our results reveal previously unobserved inhibitor binding modes and promising scaffolds for the generation of selective GMII inhibitors.
2020-05-28 | Pharmacological Chaperones for the Treatment of α-Mannosidosis.
α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5 N,6 O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2 B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation.
2019-09-03 | Intranasal dexmedetomidine and intravenous ketamine for procedural sedation in a child with alpha-mannosidosis: a magic bullet?
Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors.we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 μg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred.intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.
cell therapies
2025-06-24 | Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis.
The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.
2023-12-04 | Allogeneic hematopoietic stem cell transplantation in a pediatric patient with alpha-mannosidosis
Alpha-mannosidosis is a rare autosomal recessive hereditary disease from the group of lysosomal storage diseases with diverse clinical manifestations, the most typical of which are neurodegenerative process, hearing loss, skeletal deformities and immunodeficiency. The only radical treatment for this disease currently is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Successfully performed allo-HSCT not only allows stoppage of the disease progression, but also leads to partial improvement in previously developed complications. The Article provides general information on the disease and demonstrates the Authors’ own experience of performing allo-HSCT in a patient with alpha-mannosidosis as well.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
2019-09-21 | Intellectual functioning in alpha‐mannosidosis
Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene MAN2B1. Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha-mannosidosis (ages 8-59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha-mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.
2018-03-01 | A Decade of Low Transplant-Related Morbidity and Mortality in Children with Inherited Metabolic Diseases: A Report From a Single Metabolic Transplant Centre in the Europe
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMD). We examined the outcome of children with IMD received first HCT at Royal Manchester ChildrenÕs hospital from 1985 to 2016, a national metabolic transplant center in the United Kingdom. Cox proportional-hazard models were used to examine the predictors for overall survival. 137 children with IMD were included in this analysis (historical cohort (1985-2006), n = 65; current cohort (2007-2016), n = 72). Primary diagnoses were mucopolysaccharidoses (MPS, n = 112, 81%; MPS IH, n = 103, MPS II, n = 1, MPS III = 2, MPS VI = 6), X-linked adrenoleukodystrophy (XALD, n = 8, 6%), metachromatic leukodystrophy (n = 5, 4%), alpha mannosidosis (n = 4, 3%), Wolman disease (n = 3, 2%) and others (n = 5, 4%). The median age at transplant was 14.4 (range 1.6-220.7) months. Fifty-four children (40%) received relative donor HCT (marrow, n = 43 (78%), apheresis, n = 11 (20%) and cord blood (CB) = 2 (2%)) while 83 (60%) had unrelated donor HCT (marrow, n = 31 (37%), apheresis, n = 9 (11%) and CB, n = 43 (52%)). The estimated 5-year OS improved from 65% (95% CI, 53-76%) in the historical cohort to 91% (95%CI, 81-96%) in the current cohort (P < .001). Male (HR .35, 95%CI, .15-.81, P = .01) and grade III-IV GVHD (HR 5.10, 95%CI, 1.72-15.14, P = .003) were predictors for overall survival. In current cohort, none of the pre-transplant factors, transplant factors and transplant related complications were associated with OS. The estimated 5-year OS in children transplanted in the current cohort was 100% for XALD (n = 5), 98% (95% CI, 83%-98%) for MPS IH (n = 55) and 75% (95% CI, 42-92%) for other IMD. The estimated one-year TRM reduced from 23% (95% CI, 13-40%) in the historical cohort to 7% (95% CI, 3-18%) for current cohort (P = .006). The estimated 5-year engrafted survival (ES) has doubled from 41% (95% CI, 29-53%) in the historical cohort to 86% (95% CI, 75-92%) in the current cohort (P < .001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P < .001). Thirteen out of 18 patients (71%) in the historical cohort and all four patients (100%) in the current cohort receiving a second transplant were alive-and-engrafted. Of 82 survivors followed up at Manchester, 80% had full chimerism (_95% donor chimerism) while 20% had mixed chimerism (20-94% donor chimerism). Despite the limitation of a single centre, our findings reiterated the observation of HCT is a safe and life-long therapy for children with IMD. The outcome of a second transplant is good.
gene therapies
2026-01-22 | Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant.
Alpha-mannosidosis is a rare lysosomal storage disorder caused by MAN2B1 mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children. This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017-2025). Diagnosis was confirmed by enzyme assay and MAN2B1 testing. Clinical and imaging data were collected from medical records. A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic MAN2B1 variants, including one novel variant [c.830C > T (p.Pro277Leu)]. Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.
2025-09-02 | Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease.
The lysosomal storage disease alpha-mannosidosis (AMD) is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Animal models of lysosomal diseases have demonstrated the benefit of early treatment; however, many human diagnoses occur after patients are symptomatic. We demonstrate here partial correction of the globally distributed storage lesions by infusion of a high dose of adeno-associated virus 1-feline alpha-mannosidase into the cerebrospinal fluid via the cisterna magna in the gyrencephalic AMD cat brain at different ages, corresponding with different stages of disease progression. Significant improvements in clinical parameters were observed, and partial correction was documented pre mortem by non-invasive magnetic resonance spectroscopy and diffusion tensor imaging. Post mortem analysis demonstrated that higher levels of lysosomal alpha-mannosidase activity in animals treated at 12 weeks of age did not translate into increased correction of lysosomal storage lesions throughout the brain when compared with animals treated at earlier time points. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes.
2025-08-08 | A Review on the Structure-function Relationship of Class II α-Mannsoidases
Of fundamental importance to every function an enzyme or a protein performs is its three-dimensional structure. The structure plays a crucial, though often subtle, role in catalysis. The conformational changes in enzymes are often small, and even these small changes could be significant. Glycosylation modifications of proteins and glycan hydrolysis are critical for protein function in biological processes. Aberrations in glycosylation enzymes are linked to lysosomal storage disorders (LSD), immune interactions, congenital disorders, and tumour progression. Alpha-Mannosidases Class 2B is a lysosomal hydrolase. Dysfunction of this has been implicated as a causative factor in mannosidosis, a lysosomal storage disorder characterized by cognitive impairment, hearing loss, and immune system and skeletal anomalies. Despite decades of research, its role in pathogenic infections, autoimmune conditions, cancers, and neurodegenerative pathologies is highly ambiguous. Although many Class II α-mannosidases have been reported from various sources but not many of them have been characterized structurally. Through the combined efforts of various types of spectroscopies and protein crystallography, structure-function relationship studies in some Class II α-mannosidases from various sources have been carried out, and the same has been reported. The structure of Class II α-mannosidases from different sources has revealed the involvement of various types of folding of the protein, the presence of metal ions such as Zn+ in the active site, and their role in substrate specificity and catalytic mechanism is reviewed here.
2024-07-01 | Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.
Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.
2020-07-01 | Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy
Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood-brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.
proteins
2021-01-28 | In Vitro N-Glycan Mannosyl-Phosphorylation of a Therapeutic Enzyme by Using Recombinant Mnn14 Produced from Pichia pastoris.
Enzyme replacement therapy for lysosomal storage diseases usually requires recombinant enzymes containing mannose-6-phosphate (M6P) glycans for cellular uptake and lysosomal targeting. For the first time, a strategy is established here for the in vitro mannosyl-phosphorylation of high-mannose type N-glycans that utilizes a recombinant Mnn14 protein derived from Saccharomyces cerevisiae. Among a series of N-terminal- or C-terminal-deleted recombinant Mnn14 proteins expressed in Pichia pastoris, rMnn1477-935 with deletion of N-terminal 76 amino acids spanning the transmembrane domain (46 amino acids) and part of the stem region (30 amino acids), showed the highest level of mannosyl-phosphorylation activity. The optimum reaction conditions for rMnn1477-935 were determined through enzyme assays with a high-mannose type N-glycan (Man8GlcNAc2) as a substrate. In addition, rMnn1477-935 was shown to mannosyl-phosphorylate high-mannose type Nglycans (Man7-9GlcNAc2) on recombinant human lysosomal alpha-glucosidase (rhGAA) with remarkably high efficiency. Moreover, the majority of the resulting mannosyl-phosphorylated glycans were bis-form which can be converted to bis-phosphorylated M6P glycans having a superior lysosomal targeting capability. An in vitro N-glycan mannosyl-phosphorylation reaction using rMnn1477-935 will provide a flexible and straightforward method to increase the M6P glycan content for the generation of "Biobetter" therapeutic enzymes.
small molecules
2024-03-20 | Molecular basis of neurocognitive dysfunction and psychosis in Alpha-Mannosidosis
A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines, proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the improvement of neurocognitive symptoms in affected AM individuals.
2023-10-06 | A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency.
A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. A whole genome sequence generated with DNA from the affected dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis. In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. Thus, it appears that storage body autofluorescence and subunit c accumulation are not unique to the NCLs. Consistent with generalized lysosomal impairment, the affected dog exhibited accumulations of intracellular inclusions with varied and complex ultrastructural features characteristic of autophagolysosomes. Impaired autophagic flux may be a general feature of this class of disorders that contributes to disease pathology and could be a target for therapeutic intervention. In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband.
2021-04-15 | Manno-epi-cyclophellitols Enable Activity-Based Protein Profiling of Human α-Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors.
Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce α-mannosidosis-like symptoms. Despite many structural and mechanistic studies of GMII, we still lack a potent and selective inhibitor of this enzyme. Here, we synthesized manno-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of α-mannosidases from both human cell lysate and mouse tissue extracts. Synthesized probes also facilitated a fluorescence polarization-based screen for dGMII inhibitors. We identified seven previously unknown inhibitors of GMII from a library of over 350 iminosugars and investigated their binding modalities through X-ray crystallography. Our results reveal previously unobserved inhibitor binding modes and promising scaffolds for the generation of selective GMII inhibitors.
2020-05-28 | Pharmacological Chaperones for the Treatment of α-Mannosidosis.
α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5 N,6 O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2 B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation.
2019-09-03 | Intranasal dexmedetomidine and intravenous ketamine for procedural sedation in a child with alpha-mannosidosis: a magic bullet?
Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors.we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 μg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred.intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.
cell therapies
2025-06-24 | Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis.
The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.
2023-12-04 | Allogeneic hematopoietic stem cell transplantation in a pediatric patient with alpha-mannosidosis
Alpha-mannosidosis is a rare autosomal recessive hereditary disease from the group of lysosomal storage diseases with diverse clinical manifestations, the most typical of which are neurodegenerative process, hearing loss, skeletal deformities and immunodeficiency. The only radical treatment for this disease currently is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Successfully performed allo-HSCT not only allows stoppage of the disease progression, but also leads to partial improvement in previously developed complications. The Article provides general information on the disease and demonstrates the Authors’ own experience of performing allo-HSCT in a patient with alpha-mannosidosis as well.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
2019-09-21 | Intellectual functioning in alpha‐mannosidosis
Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene MAN2B1. Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha-mannosidosis (ages 8-59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha-mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.
2018-03-01 | A Decade of Low Transplant-Related Morbidity and Mortality in Children with Inherited Metabolic Diseases: A Report From a Single Metabolic Transplant Centre in the Europe
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMD). We examined the outcome of children with IMD received first HCT at Royal Manchester ChildrenÕs hospital from 1985 to 2016, a national metabolic transplant center in the United Kingdom. Cox proportional-hazard models were used to examine the predictors for overall survival. 137 children with IMD were included in this analysis (historical cohort (1985-2006), n = 65; current cohort (2007-2016), n = 72). Primary diagnoses were mucopolysaccharidoses (MPS, n = 112, 81%; MPS IH, n = 103, MPS II, n = 1, MPS III = 2, MPS VI = 6), X-linked adrenoleukodystrophy (XALD, n = 8, 6%), metachromatic leukodystrophy (n = 5, 4%), alpha mannosidosis (n = 4, 3%), Wolman disease (n = 3, 2%) and others (n = 5, 4%). The median age at transplant was 14.4 (range 1.6-220.7) months. Fifty-four children (40%) received relative donor HCT (marrow, n = 43 (78%), apheresis, n = 11 (20%) and cord blood (CB) = 2 (2%)) while 83 (60%) had unrelated donor HCT (marrow, n = 31 (37%), apheresis, n = 9 (11%) and CB, n = 43 (52%)). The estimated 5-year OS improved from 65% (95% CI, 53-76%) in the historical cohort to 91% (95%CI, 81-96%) in the current cohort (P < .001). Male (HR .35, 95%CI, .15-.81, P = .01) and grade III-IV GVHD (HR 5.10, 95%CI, 1.72-15.14, P = .003) were predictors for overall survival. In current cohort, none of the pre-transplant factors, transplant factors and transplant related complications were associated with OS. The estimated 5-year OS in children transplanted in the current cohort was 100% for XALD (n = 5), 98% (95% CI, 83%-98%) for MPS IH (n = 55) and 75% (95% CI, 42-92%) for other IMD. The estimated one-year TRM reduced from 23% (95% CI, 13-40%) in the historical cohort to 7% (95% CI, 3-18%) for current cohort (P = .006). The estimated 5-year engrafted survival (ES) has doubled from 41% (95% CI, 29-53%) in the historical cohort to 86% (95% CI, 75-92%) in the current cohort (P < .001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P < .001). Thirteen out of 18 patients (71%) in the historical cohort and all four patients (100%) in the current cohort receiving a second transplant were alive-and-engrafted. Of 82 survivors followed up at Manchester, 80% had full chimerism (_95% donor chimerism) while 20% had mixed chimerism (20-94% donor chimerism). Despite the limitation of a single centre, our findings reiterated the observation of HCT is a safe and life-long therapy for children with IMD. The outcome of a second transplant is good.
gene therapies
2026-01-22 | Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant.
Alpha-mannosidosis is a rare lysosomal storage disorder caused by MAN2B1 mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children. This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017-2025). Diagnosis was confirmed by enzyme assay and MAN2B1 testing. Clinical and imaging data were collected from medical records. A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic MAN2B1 variants, including one novel variant [c.830C > T (p.Pro277Leu)]. Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.
2025-09-02 | Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease.
The lysosomal storage disease alpha-mannosidosis (AMD) is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Animal models of lysosomal diseases have demonstrated the benefit of early treatment; however, many human diagnoses occur after patients are symptomatic. We demonstrate here partial correction of the globally distributed storage lesions by infusion of a high dose of adeno-associated virus 1-feline alpha-mannosidase into the cerebrospinal fluid via the cisterna magna in the gyrencephalic AMD cat brain at different ages, corresponding with different stages of disease progression. Significant improvements in clinical parameters were observed, and partial correction was documented pre mortem by non-invasive magnetic resonance spectroscopy and diffusion tensor imaging. Post mortem analysis demonstrated that higher levels of lysosomal alpha-mannosidase activity in animals treated at 12 weeks of age did not translate into increased correction of lysosomal storage lesions throughout the brain when compared with animals treated at earlier time points. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes.
2025-08-08 | A Review on the Structure-function Relationship of Class II α-Mannsoidases
Of fundamental importance to every function an enzyme or a protein performs is its three-dimensional structure. The structure plays a crucial, though often subtle, role in catalysis. The conformational changes in enzymes are often small, and even these small changes could be significant. Glycosylation modifications of proteins and glycan hydrolysis are critical for protein function in biological processes. Aberrations in glycosylation enzymes are linked to lysosomal storage disorders (LSD), immune interactions, congenital disorders, and tumour progression. Alpha-Mannosidases Class 2B is a lysosomal hydrolase. Dysfunction of this has been implicated as a causative factor in mannosidosis, a lysosomal storage disorder characterized by cognitive impairment, hearing loss, and immune system and skeletal anomalies. Despite decades of research, its role in pathogenic infections, autoimmune conditions, cancers, and neurodegenerative pathologies is highly ambiguous. Although many Class II α-mannosidases have been reported from various sources but not many of them have been characterized structurally. Through the combined efforts of various types of spectroscopies and protein crystallography, structure-function relationship studies in some Class II α-mannosidases from various sources have been carried out, and the same has been reported. The structure of Class II α-mannosidases from different sources has revealed the involvement of various types of folding of the protein, the presence of metal ions such as Zn+ in the active site, and their role in substrate specificity and catalytic mechanism is reviewed here.
2024-07-01 | Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.
Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.
2020-07-01 | Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy
Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood-brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.
proteins
2021-01-28 | In Vitro N-Glycan Mannosyl-Phosphorylation of a Therapeutic Enzyme by Using Recombinant Mnn14 Produced from Pichia pastoris.
Enzyme replacement therapy for lysosomal storage diseases usually requires recombinant enzymes containing mannose-6-phosphate (M6P) glycans for cellular uptake and lysosomal targeting. For the first time, a strategy is established here for the in vitro mannosyl-phosphorylation of high-mannose type N-glycans that utilizes a recombinant Mnn14 protein derived from Saccharomyces cerevisiae. Among a series of N-terminal- or C-terminal-deleted recombinant Mnn14 proteins expressed in Pichia pastoris, rMnn1477-935 with deletion of N-terminal 76 amino acids spanning the transmembrane domain (46 amino acids) and part of the stem region (30 amino acids), showed the highest level of mannosyl-phosphorylation activity. The optimum reaction conditions for rMnn1477-935 were determined through enzyme assays with a high-mannose type N-glycan (Man8GlcNAc2) as a substrate. In addition, rMnn1477-935 was shown to mannosyl-phosphorylate high-mannose type Nglycans (Man7-9GlcNAc2) on recombinant human lysosomal alpha-glucosidase (rhGAA) with remarkably high efficiency. Moreover, the majority of the resulting mannosyl-phosphorylated glycans were bis-form which can be converted to bis-phosphorylated M6P glycans having a superior lysosomal targeting capability. An in vitro N-glycan mannosyl-phosphorylation reaction using rMnn1477-935 will provide a flexible and straightforward method to increase the M6P glycan content for the generation of "Biobetter" therapeutic enzymes.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
4 orphan drug designations for Alpha-mannosidosis, including 2 approved therapies.
4 orphan drug designations for Alpha-mannosidosis, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous peripheral blood-derived CD34+ haematopoietic stem and progenitor cells transduced with a lentiviral vector containing the human MAN2B1 gene | gene therapies | EMA | 2025-12-09 | — | Fondazione Telethon Ets |
adeno-associated virus serotype 6 containing human LAMAN cDNA | gene therapies | FDA | 2018-02-15 | — | Stephen G. Kaler, MD |
velmanase alfa-tycv [Lamzede] | proteins | FDA | 2006-02-02 | 2023-02-16 | Chiesi USA, Inc. |
Recombinant human α-Mannosidase [Lamzede] | proteins | EMA | 2005-01-26 | 2018-03-27 | Chiesi Farmaceutici S.p.A. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.