DeCure for Proximal spinal muscular atrophy type 3
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Proximal spinal muscular atrophy type 3 — 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 moduleProximal spinal muscular atrophy type 3 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
Current lead
No approved-drug candidate for proximal spinal muscular atrophy type 3 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
NLR family apoptosis inhibitory protein (NAIP) — NAIP 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 atpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8FVU · 3.6 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2008 study of ten patients with SMA IIIb followed for at least ten years, muscle strength declined by roughly one MRC grade every five years, with some muscles appearing stationary for five- to ten-year periods. The sequence of weakness was consistent across patients: triceps, then biceps and deltoid in the upper limbs; thigh adductors, then iliopsoas, quadriceps femoris, hamstrings, thigh abductors, and gluteus maximus in the lower limbs. The authors noted that the slowness of deterioration may have implications for clinical trial design.
A 2007 review of clinical trials in SMA reported that phenylbutyrate showed promise in a mouse model and an open-label pilot study but was not effective in a phase 2 trial. Valproate was noted to have induced promising motor-function improvement in patients, and hydroxyurea was reported to enhance splice function and increase nuclear gems. The review concluded that discoveries about SMA genetics had identified potential pharmacotherapy targets but that better treatments were still needed.
A 2019 mini-review on drug repositioning for SMA noted that the first SMN genetic therapy had been approved and that other SMN-dependent treatments were not far behind. It stated that not all SMA patients would reap maximal benefit from these treatments due to limited accessibility, high costs, and differential effects depending on timing of administration and disease severity. The review discussed the potential of repurposing drugs used for neurodegenerative, neuromuscular, and muscle disorders, but provided no clinical data from such repurposing in SMA patients.
A 2020 overview of new SMA treatments stated that several phase 1–3 studies, including three double-blind randomised placebo-controlled trials, had demonstrated efficacy of disease-modifying approaches including gene replacement therapy, antisense oligonucleotides, and splicing modifiers. It noted that no biomarkers were available to distinguish responders from non-responders, and that early treatment was essential for maximum efficacy. A 2019 review of early treatment in SMA reported that prognosis for SMA type 1 had shifted from rapidly lethal to long-term event-free survival with acquisition of motor milestones, and that SMA type 2 prognosis had shifted from slow progressive deterioration to long-term stability. It identified the only predictive factor for treatment success as age at treatment initiation, closely related to disease duration, and noted large heterogeneity in clinical response ranging from absence of response to impressive improvement.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2007 · 320 citations
The changing natural history of spinal muscular atrophy type 1
AbstractBACKGROUND: Noninvasive ventilation has become increasingly available to spinal muscular atrophy (SMA) patients since the early 1990 s. This is expected to have improved survival for SMA type 1 patients. OBJECTIVE: To assess whether there has been a change in survival in patients with SMA type 1 between 1980 and 2006. METHODS: We used deidentified, family-reported data from participants in the International Spinal Muscular Atrophy Patient Registry and obtained additional clinical information through a mail-in questionnaire. One hundred forty-three patients with SMA type 1 were included in the analysis. Survival of patients born in 1995-2006 (n = 78) was compared with that of patients born in 1980-1994 (n = 65), using the Kaplan-Meier method and Cox proportional hazards models with age at death as the outcome. RESULTS: Patients born in 1995 though 2006 had significantly increased survival compared with those born in 1980-1994 (log-rank test, p < 0.001). In a Cox model, patients born in 1995-2006 had a 70% reduction in the risk of death compared with those born in 1980-1994 (hazard ratio [HR] 0.3, 95% CI 0.2-0.5, p < 0.001) over a mean follow-up of 49.9 months (SD 61.1, median 22.0). However, when controlling for demographic and clinical care variables, year of birth was no longer significantly associated with age at death (HR 1.0, 95% CI 0.6-1.8, p = 0.9), whereas ventilation for more than 16 h/d, use of a mechanical insufflation-exsufflation device, and gastrostomy tube feeding showed a significant effect in reducing the risk of death. CONCLUSION: Survival in spinal muscular atrophy type 1 patients has increased in recent years, in relation to the growing trend toward more proactive clinical care.
Therapeutics and Clinical Risk Management · 2019 · 200 citations · open access
<p>Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives</p>
AbstractRecent advances in the treatment of spinal muscular atrophy (SMA) have dramatically altered prognosis. Rather than a rapidly lethal disease, SMA type 1, the most severe form with the earliest onset of SMA, has become a disease in which long-term event-free survival with the acquisition of important motor milestones is likely. Prognosis for patients with SMA type 2 has shifted from slow and progressive deterioration to long-term stability. Nevertheless, there is a large heterogeneity in terms of clinical response to currently available treatments, ranging from absence of response to impressive improvement. The only factor identified that is predictive of treatment success is the age of the patient at the initiation of treatment, which is closely related to disease duration. The aim of this paper is to review available evidence that support early intervention using currently available treatment approaches.
Expert Opinion on Pharmacotherapy · 2020 · 125 citations
New treatments in spinal muscular atrophy: an overview of currently available data
AbstractIntroduction: Spinal muscular atrophy (SMA) is one of the most common inherited neuromuscular disorders. It causes progressive muscle weakness and results in significant disability. Until recently, there were no drugs available for the treatment of SMA. Several phase 1–3 studies, including three double-blind randomized placebo-controlled studies have demonstrated the efficacy of disease-modifying approaches including gene replacement therapy, antisense oligonucleotides, and splicing modifiers.Areas covered: This article covers the publically available data on therapeutic strategies that address the underlying cause of SMA and clinical data available on approved treatments and drugs in the pipeline.Expert opinion: The newer therapeutic options in SMA have a good safety profile and deliver a therapeutic benefit in most patients. It is essential that the recommended standards of care are delivered along with the drugs for the best outcomes. No biomarkers to distinguish responders from non-responders are available; it is important that biomarkers be identified. Early treatment is essential for the maximum efficacy of the newly available treatments.
AbstractOBJECTIVE: To assess the natural progression of muscle weakness in spinal muscular atrophy (SMA) IIIb. METHODS: Ten patients with SMA IIIb were followed for at least 10 years. Age at disease onset varied between 9 and 18 years. Patients were initially seen 2 to 10 years after disease onset. They were evaluated at approximately 2, 5, 10, 15, and 20 years of disease duration depending on the timing of their initial visit after onset. Medical Research Council (MRC) scale was used with particular attention to proximal muscles. RESULTS: The MRC grade declined with years in all of the muscles. The decline was usually not more than by one MRC grade for each 5-year period. There were 5-10 year periods when some muscles appeared to remain stationary. The succession of weakness was first triceps, then biceps and deltoid for upper extremity muscles and first thigh adductors, then iliopsoas, then quadriceps femoris, then hamstrings, thigh abductors, and gluteus maximus for lower extremity muscles. There was a remarkable uniformity between patients in the MRC grade for each muscle at each stage: in the first 5 years of the disease, triceps, iliopsoas, thigh adductors, and quadriceps femoris were the muscles which had noticeable weakness. CONCLUSIONS: These findings show that strength in spinal muscular atrophy IIIb decreases over time, explaining the progressive functional loss. The sequence of weakness in the lower extremities suggests that the disease starts segmentally involving the upper lumbar segments of the medulla spinalis initially. The slowness of the deterioration may have implications for clinical trials.
Current Opinion in Pediatrics · 2007 · 35 citations
Clinical trials in spinal muscular atrophy
AbstractPURPOSE OF REVIEW: Spinal muscular atrophy is a neuromuscular disorder manifesting as weakness and hypotonia across a broad spectrum of severity. Mutations in the telomeric copy of the survival motor neuron gene (SMN1) cause the autosomal recessive form. Disease severity is modified by the number of centromeric copies of the gene (SMN2) and the quantity of survival motor neuron protein. This has given rise to a number of treatment strategies. RECENT FINDINGS: Histone deacetylase inhibitors appear to increase the expression of SMN2, with an increase in survival motor neuron protein in various cell types. Clinical trials have been performed with three histone deacetylase inhibitors which are already licensed in the USA. Phenylbutyrate showed promise in a mouse model and an open-label pilot study, but was not effective in a phase 2 trial. Valproate may enhance transcription and reverse SMN2 splicing pattern, and has induced promising motor-function improvement in patients. Hydroxyurea may enhance splice function and increase the number of nuclear 'gems', small nuclear organelles in which survival motor neuron protein concentrates. SUMMARY: Discoveries regarding the genetics and pathogenesis of spinal muscular atrophy have identified potential targets for pharmacotherapy, raising hope that better treatments will eventually be developed.
Future Neurology · 2019 · 9 citations · open access
Teaching An Old Drug New Tricks: Repositioning Strategies for Spinal Muscular atrophy
AbstractSpinal muscular atrophy (SMA) is a childhood disorder caused by loss of the SMN gene. Pathological hallmarks are spinal cord motor neuron death, neuromuscular junction dysfunction and muscle atrophy. The first SMN genetic therapy was recently approved and other SMN-dependent treatments are not far behind. However, not all SMA patients will reap their maximal benefit due to limited accessibility, high costs and differential effects depending on timing of administration and disease severity. The repurposing of commercially available drugs is an interesting strategy to ensure more rapid and less expensive access to new treatments. In this mini-review, we will discuss the potential and relevance of repositioning drugs currently used for neurodegenerative, neuromuscular and muscle disorders for SMA.
Arquivos de Neuro-Psiquiatria · 2023 · 0 citations · open access
Intrathecal administration of Nusinersen in children and adolescent SMA type 1 and 2
AbstractBackground: Spinal muscular atrophy (SMA) is an autosomal-recessive disorder resulting in progressive muscle weakness. In August 2017, the Agência Nacional de Vigilância Sanitária (ANVISA) approved the first treatment for SMA, a drug named nusinersen that is administered intrathecally. However, many patients with SMA have neuromuscular scoliosis or spinal instrumentation resulting in challenging intrathecal access. Many centers use radiological methods to guide lumbar puncture, such as ultrasound, videofluoroscopy or tomography, but these methods are often available only in referral centers.
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.
