DeCure for Infantile-onset X-linked spinal muscular atrophy
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for infantile-onset X-linked spinal muscular atrophy — 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 moduleInfantile-onset X-linked spinal muscular atrophy 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 infantile-onset x-linked 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
ubiquitin like modifier activating enzyme 1 (UBA1) — UBA1 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 ampdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9MC5 · 3.29 Å · ligand ADENOSINE MONOPHOSPHATE (AMP). Experimental structure, not a prediction.
What the evidence adds up to
The majority of patients with chronic infantile and juvenile forms of spinal muscular atrophy survive to adult life, according to a 1981 review of 44 patients followed for an average of 17 years after diagnosis. Subdivision into four functional groups, based on maximal physical function achieved, correlates with the onset and severity of secondary limb and spine deformity. A 2007 review notes that spinal muscular atrophy is a neuromuscular disorder caused by mutations in the telomeric copy of the SMN1 gene, with disease severity modified by the number of centromeric SMN2 copies. Histone deacetylase inhibitors have been tested: 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 may enhance splice function and increase nuclear gems.
The first SMN genetic therapy was approved in 2016, based on a pivotal study terminated early because more than half of infants receiving nusinersen reached a motor milestone compared to none receiving placebo. Risdiplam showed impressive results in toddlers. Both drugs were approved without an upper age limit, but no randomised clinical trial of efficacy has been conducted in people older than 25 years. The 2023 commentary by Fontanelli et al. notes that adult patients are currently treated with nusinersen or risdiplam, and that while the drugs are generally well tolerated, they are not without side effects — nusinersen requires a lumbar puncture every four months, risdiplam a daily dose — and are among the most expensive drugs in the world. The authors argue that prescribing these drugs to older patients without trial evidence should not be seen as an open-label clinical trial, and that randomised trials specifically for older populations are needed.
A 2021 study using patient tissues and a mouse model found that motor neuron axons were already developmentally delayed in the fetus and experienced early postnatal death. In utero therapeutic intervention prevented motor neuron degeneration and improved axonal function and motor behaviour in mice, suggesting fetal treatment might increase efficacy of current therapies. A 2007 report states that SMA type 1 remains a fatal illness for which there is not yet a cure, and the focus of care continues to be symptomatic. What is still missing are randomised clinical trials assessing efficacy outcomes in older patients, international consensus guidance for treatment across varied clinical phenotypes, and evidence on whether fetal intervention can be translated to humans.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Bone and Joint Surgery - British Volume · 1981 · 116 citations
Functional classification and orthopaedic management of spinal muscular atrophy
AbstractThe majority of patients with chronic infantile and juvenile forms of spinal muscular atrophy survive to adult life. Forty-four patients have been reviewed at an average of 17 years after diagnosis. The subdivision of patients into four groups, based on the maximal physical function developed by the individual, correlates well with the onset and severity of secondary deformity of the limbs and spine. This information allows anticipation of the problems and plans for their treatment to be made from early childhood. After analysis of the orthotic and surgical treatment received by these patients, a specific programme of care is recommended for each of the functional groups.
Archives of Pediatrics and Adolescent Medicine · 1988 · 71 citations
X-linked Infantile Spinal Muscular Atrophy
AbstractFour male infants from three sibships in an extended family were noted to have hypotonia, areflexia, and congenital joint contractures. The findings of electromyography and muscle histology were consistent with infantile spinal muscular atrophy (SMA). Pedigree analysis suggests that this disorder represents an X-linked, recessive form of SMA. Findings in similar kindreds may explain the previously reported increased male-female ratio in infantile SMA.
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.
Spinal Muscular Atrophy: A Potential Target for In Utero Therapy
AbstractSpinal muscular atrophy (SMA) is a life-threatening autosomal recessive disease that leads to progressive muscle weakness and atrophy, respiratory insufficiency and scoliosis. SMA is currently the most common monogenic cause of infant mortality. Amazing advancements have been made in the therapeutic options available for these children since 2016. What has also become clear is that the earlier the treatment is administered, the better the clinical outcome. For several reasons, which we will review in this chapter, SMA may be an excellent disease candidate for in utero therapy.
European Journal of Neurology · 2023 · 2 citations · open access
Spinal muscular atrophy: Should we prescribe approved drugs to cohorts of patients in which they are unproven?
AbstractThe pivotal study that led to the approval of the first drug for spinal muscular atrophy (SMA) in 2016 was terminated early because of its striking results: more than half of infants receiving nusinersen reached a motor milestone, compared to none of those receiving placebo [1]. Similarly, risdiplam showed impressive results in terms of outcome in toddlers [2]. What both these drugs have in common is that the studies that led to their approval were essentially based on infants with SMA type 1, with evidence, albeit less marked, for children and young adults with SMA types 2 and 3 [3]. Although these studies focused only on a specific portion of the population affected with SMA, the US Food and Drug Administration and the European Medicine Agency approved both treatments without any upper age limit. Nowadays, adult patients are currently treated either with nusinersen or risdiplam, although no randomized clinical trial of efficacy has been conducted in people older than 25 years. As regulatory agencies have not restricted the indications for these drugs, adult patients are fully entitled to receive these potentially beneficial treatments, and to refrain from prescribing them could theoretically result in a denial of cure. On the other hand, the act of prescribing a drug is always the result of a balance of risk and benefits. In this regard, since these drugs are generally well tolerated, and given that the risk is generally low, the risk–benefit ratio favors the benefits even for small and subtle positive effects, and clinicians may decide to opt for the treatment in the hope of a result. This bona fide attitude, however, should be regarded cautiously. Although well tolerated, these drugs are not without side effects [1-3] and the burden associated with these therapies (i.e., a lumbar puncture every 4 months in the case of nusinersen, or a daily dose of risdiplam) should also be carefully taken into consideration. Of equal importance, these therapies are highly expensive—being in fact two of the most expensive drugs in the world—and their prescription significantly impacts on the financial resources of national health services. The wide range of data obtained by extended prescriptions will undoubtedly shed light on the effect of these molecules in older patients, but this “faculty to prescribe” should not be seen as an “open-label clinical trial” since such evidence (or, often, “impressions”), which remains outside well-defined protocols, is less rigorous regarding the outcomes of standardized randomized, double-blind, clinical trials. Healthcare professionals should carefully evaluate the available evidence specific to the different patient cohorts in which they are intending to use the therapies; this should include an overall evaluation of the risks and burden of the treatment, and patients should always be informed about current evidence for their specific condition. It is therefore of paramount importance to design randomized clinical trials specifically to assess efficacy outcomes in the older population, as well as to determine international consensus guidance for the use of these innovative treatments in a population with such varied clinical phenotypes. Lorenzo Fontanelli: Conceptualization; writing – original draft; validation; writing – review and editing; supervision; investigation. Giulia Di Rauso: Validation; writing – review and editing. Gabriele Bellini: Conceptualization; supervision; writing – original draft; writing – review and editing; investigation. Authors have no conflict of interest to declare. Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Antzina: revista de genealogía vasca e historia local · 2007 · 0 citations
Ser Navarro: Naturalizaciones
AbstractSpinal muscular atrophy (SMA) is the most common childhood neurodegenerative disease. We report an infant with SMA type 1 and discuss the recent developments in SMA genetics, pathophysiology, and possible treatment options. Because SMA type 1 remains a fatal illness for which there is not yet a cure, the focus of patient care continues to be symptomatic. Thus, the most appropriate aspects of care at present and future are also discussed.
AbstractGene Therapy
Gene therapy approaches hold promise for the treatment of spinal muscular atrophy (SMA). However, these therapies show variable clinical response, and treatment at earlier ages is associated with better outcome. Using tissues from patients and a mouse model, Kong et al. found that motor neuron axons were already developmental delayed in the fetus and experienced early postnatal death. In utero therapeutic intervention prevented motor neuron degeneration and improved axonal function and motor behavior in mice. The results suggest that fetal treatment might increase the efficacy of current therapies for SMA.
Sci. Transl. Med. 13 , eabb6871 (2021).
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.
