DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Fabry disease — screening already-approved drugs against its 6-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleFabry disease maps to a 6-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
Current lead
No approved-drug candidate for fabry disease is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
galactosidase alpha (GLA) — GLA is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 2pedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3HG3 · 1.9 Å · ligand NONAETHYLENE GLYCOL (2PE). Experimental structure, not a prediction.
What the evidence adds up to
In a 2002 randomised double-blind placebo-controlled trial, 26 hemizygous Fabry patients (age 19–47) received enzyme replacement therapy (recombinant alpha-galactosidase A) or placebo by intravenous infusion every two weeks for six months. Regional cerebral blood flow was measured with PET before and after treatment. Fabry patients had a significantly greater increase in blood flow following visual stimulation and acetazolamide challenge compared to controls, and the time for recovery of the cerebral vasculature after acetazolamide was prolonged. These abnormal cerebrovascular responses decreased significantly after enzyme replacement therapy, and the prolonged recovery time also improved. The authors concluded that enzyme replacement reverses the exaggerated cerebrovascular response in Fabry disease.
A 2003 review noted that enzyme replacement therapy with recombinant alpha-galactosidase A was the only specific treatment available at that time. Clinical trials had shown safety and efficacy in reversing substrate storage in various tissues, and short-term responses in impaired kidney function demonstrated a clear potential to improve and stabilise symptoms. However, the review also stated that longer-term experience on clinical outcome in patients with severe vital organ involvement was still limited. The review mentioned enzyme enhancement therapy with pharmacological chaperones as an attractive approach for patients with residual enzyme activity, and gene transfer as a possible future strategy.
A 2004 report described a nonsense mutation (R220X) in the alpha-galactosidase A gene in a 41-year-old hemizygous man and his 71-year-old heterozygous mother, both presenting with renal and cardiac manifestations of Fabry disease. Typical histological findings were observed in renal biopsy from the proband and in renal and myocardial necropsy specimens from the mother. This was the first detailed report of family members with Fabry disease due to this nonsense mutation, and the study indicated that the mutation causes the typical disease in both genders.
A 2018 study of a four-generation Chinese Han family with left ventricular hypertrophy and chronic renal failure identified a novel loss-of-function mutation in exon 6 of the GLA gene, p.Asn278Lys, which completely co-segregated with the disease phenotype. The protein level of alpha-galactosidase A was significantly lower in the variant group than in the wild-type group. The pharmacological chaperone 1-deoxy-galactonojirimycin (DGJ) effectively normalised the enzyme activity of alpha-galactosidase A and its decline at the protein level in this overexpression system. The study analysed the feasibility of DGJ as a therapeutic approach for this particular GLA mutation, but no clinical trial data on DGJ in patients were provided. What remains missing is long-term clinical outcome data for enzyme replacement therapy in patients with advanced organ damage, and any clinical evidence that pharmacological chaperones such as DGJ improve patient outcomes rather than just enzyme activity in cell models.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
BMC Neurology · 2002 · 102 citations · open access
Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease
AbstractBACKGROUND: Fabry disease is a lysosomal X-linked enzyme deficiency of alpha-galactosidase A associated with an increased mortality and morbidity due to renal failure, cardiac disease and early onset stroke. METHODS: We examined the functional blood flow response of the brain after visual stimulation (reversing checkerboard pattern), and cerebral vasoreactivity following acetazolamide (15 mg/kg) with [15O]H2O and positron emission tomography (PET) in Fabry disease. Twenty-six hemizygous patients (age range 19-47 years) were enrolled in a randomized double-blind placebo-controlled 6-month trial of enzyme replacement therapy administered by intravenous infusion every two weeks. Regional cerebral blood flow (rCBF) was measured with PET at the beginning and end of the trial. RESULTS: Fabry patients had a significantly greater increase in rCBF following visual stimulation and acetazolamide challenge compared to controls. Visual reactivity was normal. The time for recovery of the cerebral vasculature following acetazolamide was prolonged in Fabry patients compared to controls. The abnormal rCBF response induced by visual stimulation and acetazolamide decreased significantly following enzyme replacement therapy, as did the prolonged recovery of the cerebral vasculature. CONCLUSIONS: Enzyme replacement therapy reverses the exaggerated cerebrovascular response in Fabry disease.
Current Opinion in Nephrology & Hypertension · 2003 · 14 citations
Enzyme replacement therapy in Fabry disease: clinical implications
AbstractPURPOSE OF REVIEW: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A. The lack of enzyme activity results in an intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide, in various tissues. Significant morbidity is caused by progressive effects on the vascular endothelium, heart, brain and kidney leading to end-stage renal disease. In this review we would like to give a current overview on recent advances in therapy and an outlook on future aspects in the management of Fabry disease. RECENT FINDINGS: Besides symptomatic management, enzyme replacement therapy with recombinant alpha-galactosidase A is the only specific treatment currently available. Clinical trials using recombinant alpha-galactosidase A showed safety and efficacy in reversing substrate storage in different tissues. Short-term response on clinical manifestations such as impaired kidney function demonstrates a clear potential to improve and stabilize symptoms of the disease. In patients with residual enzyme activity enzyme enhancement therapy with pharmacological chaperones seems to be an attractive approach. Enzyme replacement therapy mediated by gene transfer may become a promising alternative treatment strategy in the future. SUMMARY: Remarkable advances in the treatment of patients with Fabry disease have been made with the introduction of enzyme replacement therapy in clinical use. Although lysosomal globotriaosylceramide deposits are cleared very effectively, longer term experience on clinical outcome in patients with severe vital organ involvement is still limited.
A nonsense mutation (R220X) in the a-galactosidase A gene causes typical Fabry disease in both genders
AbstractBACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). Chronic renal failure is an important cause of death in patients with Fabry disease. We report on patients with Fabry disease (a hemizygous male and his mother) due to a nonsense mutation (R220X) in the alpha-Gal A gene. METHODS: The proband, a 41-year-old man, and his 71-year-old mother presented with renal and cardiac manifestations of Fabry disease. Histological examination and molecular analysis of the alpha-Gal A gene were performed. RESULTS: Typical histological findings of Fabry disease were observed in a renal biopsy specimen from the proband and in renal and myocardial necropsy specimens from the mother. Sequencing of a full-length alpha-Gal A cDNA from the proband indicated a C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X). Examination of genomic alpha-Gal A DNA revealed that the proband was a hemizygote and the mother was a heterozygous carrier for the mutation. CONCLUSION: This is the first detailed report of family members with Fabry disease due to a nonsense mutation (R220X) in the alpha-Gal A gene. Our study indicates that this mutation causes the typical disease in both genders.
BMC Medical Genetics · 2018 · 2 citations · open access
Identification of a novel loss-of-function mutation of the GLA gene in a Chinese Han family with Fabry disease
AbstractBACKGROUND: Fabry disease is an X-linked recessive lysosomal disorder caused by deficient enzymatic activity of α-galactosidase A (α-Gal A). The insufficient enzymatic activity leads to excessive accumulation of glycosphingolipids, the substrates of the enzyme, in lysosomes in organs and tissues. Mutations in the α-Gal A gene (GLA, Xq22) have been proven to be responsible for Fabry disease. METHODS: In this study, we report a four-generation pedigree with left ventricular hypertrophy and chronic renal failure that was diagnosed by sequencing the GLA gene. An over expression system was constructed to evaluate the function of the detected mutation. RESULTS: We identified a novel mutation in exon 6 of the GLA gene, p.Asn278Lys, which completely co-segregated with the disease phenotype. The protein level of α-Gal A was significantly lower in the variant group than in the wild-type group; additionally, the pharmacological chaperone 1-deoxy-galactonojirimycin (DGJ) effectively normalized the enzyme activity of α-Gal A and its decline at the protein level. CONCLUSIONS: This study is the first to report a novel loss-of-function mutation, p.Asn278Lys, in exon 6 of the GLA gene as a genetic aetiology for Fabry disease. In addition, we analysed the feasibility of DGJ as a therapeutic approach for this particular GLA mutation.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
