DeCure for Autosomal recessive distal spinal muscular atrophy 2
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for autosomal recessive distal spinal muscular atrophy 2 — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal recessive distal spinal muscular atrophy 2 maps to a 3-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 autosomal recessive distal spinal muscular atrophy 2 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
galactose-1-phosphate uridylyltransferase (GALT) — GALT 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 h2udrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6GQD · 1.523 Å · ligand 5,6-DIHYDROURIDINE-5'-MONOPHOSPHATE (H2U). Experimental structure, not a prediction.
What the evidence adds up to
A 1975 study of 38 patients with chronic proximal spinal muscular atrophy found that onset before age 2 years gave a recurrence risk of 1 in 5 among siblings, consistent with autosomal recessive inheritance. Among those with onset after age 2, the sibling recurrence risk was 1 in 15, and the risk to their children was 1 in 8, indicating both recessive and dominant forms, with nearly half of later-onset cases judged to be non-genetic motor neuron disease. About a third of patients never walked, and about half were in wheelchairs by age 10. Three patients had distinctive features: external ophthalmoplegia, dysarthria, or joint contractures.
A 2015 review notes that spinal muscular atrophy is one of the most common inherited neuromuscular conditions and that understanding of its genetic pathology has advanced, but it does not report any new trial results or survival data. A 2024 article states that several drugs now exist for pathogenetic treatment of SMA, but it focuses on debate over treating patients with 4 copies of the SMN2 gene, presenting data from only two such patients from a registry. No response rates, survival figures, or controlled comparisons are given.
The 1975 study predates any molecular diagnosis and grouped patients by clinical criteria alone, so its recurrence risks may not apply to genetically confirmed autosomal recessive distal spinal muscular atrophy 2. The later reviews do not address that specific subtype. What is missing is any trial or case series focused on distal spinal muscular atrophy 2, any stratification by the responsible gene (such as SIGMAR1 or other loci), and any funding for a dedicated natural history or treatment study in that population.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 1975 · 52 citations
A CLINICAL AND GENETIC STUDY OF CHRONIC PROXIMAL SPINAL MUSCULAR ATROPHY
AbstractA study of chronic proximal spinal muscular atrophy was undertaken with the main aim of obtaining empirical recurrence risks for genetic counselling. Thirty-eight patients and their families were studied. Of these, 33 had similar clinical features and onset of disease in infancy or childhood. A division of these 33 patients by onset before or after 2 years (which was equivalent to whether or not they ever walked normally) gave recurrence risks for sibs which were higher with early onset. Among the sibs of patients with onset before 2 years, the incidence of disease was 1 in 5, due to most patients having an autosomal recessive disorder. A few patients, however, were thought to represent new dominant mutations. Among the families of index patients with onset after 2 years, the incidence of disease in sibs was only 1 in 15, but among their children it as 1 in 8. Both autosomal recessive and autosomal dominant forms therefore occurred in this age group, but it was concluded that nearly half the patients with onset after 2 had non-genetic motor neuron disease. The autosomal recessive form of chronic spinal muscular atrophy generally had onset before 2 years, but occasionally after 2. About a third of the patients never walked, and about half were in wheelchairs by age 10. No genetic heterogeneity within this form was demonstrated. Three remaining patients had distinctive clinical features associated with their proximal weakness, external ophthalmoplegia in one, dysarthria in another, and joint contractures in a third. Only 2 patients had onset in adult life, one of a probable recessive disorder and the other a probable dominant disorder.
Degenerative Neurological and Neuromuscular Disease · 2015 · 2 citations · open access
Current and emerging treatment options for spinal muscular atrophy
AbstractAbstract: Spinal muscular atrophy is one of the most common inherited neuromuscular conditions; our understanding of the genetic pathology and translational research coming from this insight has made significant progress over the past decade. This short review provides the background of the disease along with the bench to bedside progress of some promising treatment options to develop better understanding of the present state of the disease. Keywords: SMN protein, neurodegenerative disease, orphan disease, therapeutics
Neuromuscular Diseases · 2024 · 1 citations · open access
Approaches to pathogenetic therapy of spinal muscular atrophy in children and newborns
AbstractSpinal muscular atrophy (SMA) is a hereditary, autosomal recessive disease that debuts at different ages. Neurological symptoms are progressive and lead to significant limitation of life activity and reduced life expectancy. Currently, there are several drugs for the pathogenetical treatment of SMA. This article reflects the evolution of clinicians’ views on the treatment of patients with SMA as scientific evidence from clinical trials and experience in managing patients in real‑world clinical practice accumulates. The biggest debate is about the treatment of patients with 4 copies of the SMN2 gene. An analysis of the “SMA Families” patient registry database was carried out; data on two patients with 4 copies of the SMN2 gene with early onset of the disease were presented.
Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany
AbstractAbstract Background The oral, selective SMN2-splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients ≥ 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1–4 SMN2 gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy. Patients and methods Patients with SMA1/2, aged ≥ 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs). Results Between March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving ≥ 1 risdiplam dose, respectively. The median (range) age was 10.5 (3–52) years in the SMA1 cohort, and 26.5 (3–60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naïve. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients. Conclusions We present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam.
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.
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