DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for alpha-mannosidosis — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAlpha-mannosidosis maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Structures already discussed alongside alpha-mannosidosis in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
What the evidence adds up to
Alpha-mannosidosis is an ultra-rare autosomal recessive disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, with a prevalence estimated at 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides leads to a heterogeneous continuum of manifestations including facial deformity, mental retardation, progressive sensorineural hearing loss, skeletal abnormalities, immunodeficiency, and neurological and psychiatric disease. Diagnosis relies on demonstrating low alpha-mannosidase activity in nucleated cells or dried blood spots, supported by genetic testing. The disease is insidiously progressive, and children are often born apparently normal, which delays treatment initiation.
Velmanase alfa, a human recombinant alpha-mannosidase, is approved in Europe for long-term treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. In the pivotal placebo-controlled rhLAMAN-05 study, a post-hoc global treatment response analysis (defined as response in ≥2 domains covering pharmacodynamic, functional, and quality of life outcomes) found that after 12 months, 87% of patients receiving velmanase alfa (n=15) achieved a response compared with 30% receiving placebo (n=10). Longer-term integrated data from the entire clinical programme (n=33) showed 88% of patients were global responders, including 100% of paediatric patients (n=19) and 71% of adult patients (n=14). In a separate case report of a 7-month-old infant with an early-onset form, velmanase alfa was administered as supportive therapy before haematopoietic stem cell transplantation. After two months, the mean relative changes from baseline in three mannosyl-oligosaccharides were -67% in urine and -53% in serum, and serum enzymatic activity one week after the first infusion was four times higher than normal values.
The same abstracts note that long-term therapeutic options also include haematopoietic stem cell transplantation and bone marrow transplantation, but that the possible benefits of these procedures must be weighed against the risk of procedure-related morbidity and mortality. The 2023 review states that additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa. The clinical heterogeneity of the disease and unspecific initial symptoms lead to diagnostic delay and accumulative morbidity. What remains missing are large-scale, long-term controlled trials that can confirm safety and efficacy across the full spectrum of disease severity, particularly for neurological manifestations, and better methods for early diagnosis and patient stratification.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Genetics and Metabolism · 2018 · 50 citations · open access
Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis
AbstractAlpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.
Early biochemical effects of velmanase alfa in a 7‐month‐old infant with alpha‐mannosidosis
AbstractAlpha mannosidosis is an ultrarare pathology with variable phenotypic manifestations, characterized by the deficiency of lysosomal alpha mannosidase which causes accumulation of neutral oligosaccharides. Until recently, the hematopoietic stem cell transplantation was the only clinical feasible therapeutic option. Only in 2018, the European Medicines Agency's committee approved the recombinant enzyme velmanase alfa for long-term treatment of non-neurological manifestations in mild and moderate forms of alpha-mannosidosis. In this study, the very early biochemical effects of enzyme replacement therapy in in a 7-month-old patient with alpha-mannosidosis were described. Velmanase alpha was administered as supporting therapy awaiting for hematopoietic stem cell transplantation, the treatment chosen for the patient because of the early onset form. The results showed that the enzyme replacement therapy was able to reduce the content of three different mannosyl-oligosaccharides monitored by tandem mass spectrometry after 2 months of treatment. In particular, the mean relative changes from baseline values were -67% in urine and -53% in serum at the latest observation. The study also showed that the enzymatic activity detected in serum 1 week after the first infusion was four times higher than the normal values and constant in the following points of observation. These findings led us to assume that velmanase alfa might be biologically active in this young patient.
International Journal of Surgery · 2023 · 5 citations · open access
Can velmanase alfa be the next widespread potential therapy for alpha-mannosidosis?
AbstractAlpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.
Clinical pharmacology and therapy · 2024 · 1 citations · open access
Alpha-mannosidosis: a diagnostic journey in patients with ultra-rare disease
AbstractAlpha-mannosidosis is a rare autosomal recessive hereditary disease characterized by lysosomal accumulation of olygosaccharides in various tissues due to deficiency of alpha-mannosidase. Low enzyme activity results from homozygous or compound heterozygous mutations of the MAN2B1 gene. Clinical manifestations of alpha-mannosidosis usually develop in childhood or adolescence and include facial deformity (Hurler-like phenotype), mental retardation, progressive sensorineural hearing loss, skeletal abnormalities, neurological and psychiatric disorders, and ocular disease. Demonstration of low activity of acid alpha-mannosidase in dried blood spots and genetic testing can be used for diagnosis. The authors present the case report of alpha-mannosidosis and discuss its pathogenesis, clinical signs and symptoms and approaches to treatment including the long-term enzyme replacement therapy with velmanasa alfa.
Greater South Information System · 2023 · 0 citations · open access
Can velmanase alfa be the next widespread potential therapy for alpha-mannosidosis?
AbstractAlpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.
Greater South Information System · 2023 · 0 citations · open access
Can velmanase alfa be the next widespread potential therapy for alpha-mannosidosis?
AbstractAlpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.
Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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