DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for spinal muscular atrophy — screening already-approved drugs against its 21-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSpinal muscular atrophy maps to a 21-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 spinal muscular atrophy 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
VRK serine/threonine kinase 1 (VRK1) — VRK1 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 anpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6AC9 · 2.07 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (ANP). Experimental structure, not a prediction.
What the evidence adds up to
Spinal muscular atrophy is caused by mutations in the SMN1 gene, with disease severity modified by the number of SMN2 copies and the quantity of survival motor neuron protein. Three orphan drugs have been approved: nusinersen, onasemnogene abeparvovec, and risdiplam. Preclinical evidence allowed a significant acceleration in the experimental phase of these drugs, but because they were authorised through accelerated programmes, post-marketing studies were required as a condition of approval. As of January 2023, 69 post-marketing studies concerning the three drugs were identified in clinicaltrials.gov and the EU PAS register. These ongoing studies aim to provide evidence on risk-benefit profiles in populations not included in pivotal trials and to investigate long-term safety and clinical benefits.
Prognosis for SMA type 1, the most severe form with earliest onset, has shifted from a rapidly lethal disease to one in which long-term event-free survival with acquisition of important motor milestones is likely. For SMA type 2, prognosis has shifted from slow and progressive deterioration to long-term stability. However, there is large heterogeneity in clinical response to available treatments, ranging from absence of response to impressive improvement. The only factor identified that predicts treatment success is the age of the patient at initiation of treatment, closely related to disease duration. No biomarkers to distinguish responders from non-responders are available.
Earlier attempts with histone deacetylase inhibitors produced mixed results. Phenylbutyrate showed promise in a mouse model and an open-label pilot study but was not effective in a phase 2 trial. Valproate induced promising motor-function improvement in patients. Hydroxyurea enhanced splice function and increased the number of nuclear gems in laboratory studies. Many patients with SMA still do not benefit from effective treatments or show limited clinical response or impact on their quality of life.
What is still missing are biomarkers to identify which patients will respond to which drug, evidence on long-term safety and efficacy in real-world populations beyond those in pivotal trials, and data on whether the approved treatments improve quality of life for the many patients who show limited clinical response.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neuromuscular Disorders · 2017 · 681 citations · open access
Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics
AbstractThis is the second half of a two-part document updating the standard of care recommendations for spinal muscular atrophy published in 2007. This part includes updated recommendations on pulmonary management and acute care issues, and topics that have emerged in the last few years such as other organ involvement in the severe forms of spinal muscular atrophy and the role of medications. Ethical issues and the choice of palliative versus supportive care are also addressed. These recommendations are becoming increasingly relevant given recent clinical trials and the prospect that commercially available therapies will likely change the survival and natural history of this disease.
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.
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.
Brain Sciences · 2023 · 19 citations · open access
Pharmacological Therapies of Spinal Muscular Atrophy: A Narrative Review of Preclinical, Clinical–Experimental, and Real-World Evidence
AbstractSpinal muscular atrophy (SMA) is a rare neuromuscular disease, with an estimated incidence of about 1 in 10,000 live births. To date, three orphan drugs have been approved for the treatment of SMA: nusinersen, onasemnogene abeparvovec, and risdiplam. The aim of this narrative review was to provide an overview of the pre- and post-marketing evidence on the pharmacological treatments approved for the treatment of SMA by identifying preclinical and clinical studies registered in clinicaltrials.gov and in the EU PAS register from their inception until the 4 January 2023. The preclinical evidence on the drugs approved for SMA allowed a significant acceleration in the experimental phase of these drugs. However, since these drugs had been authorized through accelerated programs, the conduction of post-marketing studies was requested as a condition of their marketing approval to better understand their risk-benefit profiles in real-world settings. As of the 4 January 2023, a total of 69 post-marketing studies concerning the three orphan drugs approved for SMA were identified in clinicaltrials.gov (N = 65; 94.2%) and in the EU PAS register (N = 4; 5.8%). Currently, ongoing studies are primarily aimed at providing evidence concerning the risk-benefit profile of the three drugs in specific populations that were not included in the pivotal trials and to investigate the long-term safety and clinical benefits of these drugs. Real-world data sources collecting information regarding the natural history of the disease and post-marketing surveillance of the available therapies are increasingly becoming essential for generating real-world evidence on this rare disease and its orphan drugs.
Revista médica de Chile · 2011 · 11 citations · open access
Atrofia muscular espinal: Caracterización clínica, electrofisiológica y molecular de 26 pacientes
AbstractBACKGROUND: Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder affecting the anterior horn cells of the spinal cord resulting in muscle weakness and atrophy, linked to the homozygous disruption of the survival motor neuron 1 (SMN1) gene. It is the leading genetic cause of infant death. It has been classified into three types based on the severity of symptoms. Type I SMA is the most severe form with death within the first 2 years of life. Type II and III SMA patients show intermediate and mild forms of the disorder. AIM: To describe the clinical and electrophysiological findings of 26 Chilean patients with SMA with molecular confirmation. PATIENTS AND METHODS: Retrospective multicenter analysis of patients with SMA assessed between 2003 and 2010. The diagnosis was suspected on clinical and electrophysiological criteria. Since 2006 molecular genetics confirmation was implemented in one of our centers. RESULTS: Twenty-six patients between 2 months and 18 years of age at presentation were analyzed; 15 (58%) were males. SMA I, II and III clinical criteria were observed in 4 (15.4 %), 11 (42.3%) and 11 (42.3%)patients, respectively. All had proximal muscle weakness and atrophy. Electromyography showed features of acute denervation or re-innervation with normal motor and sensory nerve conduction. Nine patients required a muscle biopsy. The genetic confirmation of the disease by PCR technique followed by restriction fragment length polymorphism method disclosed the SMN1 gene deletion in all 26 cases. All patients died secondary to respiratory failure, between eight and 14 months of life. CONCLUSIONS: An adequate clinical and molecular diagnosis of spinal muscular atrophy will help for a better management of these patients.
Journal of Neuromuscular Diseases · 2018 · 10 citations · open access
Position Statement: Sharing of Clinical Research Data in Spinal Muscular Atrophy to Accelerate Research and Improve Outcomes for Patients
AbstractRecent years have seen increasing clinical research activities in spinal muscular atrophy (SMA), involving patients, their families, clinicians, researchers, regulators and industry This has led to unprecedented advancements in understanding of genetic determinants of severity and prognosis, the natural history, outcome measures, and most importantly first marketed therapies However, many patients with SMA do not benefit yet from effective treatments or show limited clinical response or impact on their quality of life.
Asian Journal of Pharmaceutical and Clinical Research · 2017 · 0 citations · open access
HAVING A GO AT SPINAL MUSCULAR ATROPHY WITH SPINRAZA
AbstractSpinal muscular atrophy (SMA), a neurological condition which is genetically mediated is the second most common infantile disease causing morbidity and mortality next to cystic fibrosis. It is of five different types with each type having different severity outcomes. For almost three decades, only supportive measures were advocated in the treatment of SMA. Recently, Biogen’s Spinraza came out as the first disease modifying therapy to treat infantile as well as adult SMA. This review throws light on the pharmacological aspects of the drug; its approval by Food and Drug Administration and various completed clinical trials as well ongoing clinical trials.
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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