DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 54 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHereditary spastic paraplegia 54 maps to a 2-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 hereditary spastic paraplegia 54 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
phosphate cytidylyltransferase 2, ethanolamine (PCYT2) — PCYT2 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 c5pdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3ELB · 2.0 Å · ligand CYTIDINE-5'-MONOPHOSPHATE (C5P). Experimental structure, not a prediction.
What the evidence adds up to
A 2008 study mapped a novel autosomal recessive HSP locus, SPG35, to chromosome 16q21-q23.1 in a large consanguineous Omani family. The age at onset ranged from 6 to 11 years, the disease was progressive, and intellectual disability was present, with seizures in two individuals. A 20.4 Mb region of homozygosity was shared by all affected individuals, with a peak multipoint lod score of 4.86. Sequencing of two candidate genes in the region, DYNC1LI2 and VPS4A, found no disease-causing mutations.
A 2017 review of balance impairments and falls in hereditary spastic paraplegia noted that these are among the most debilitating symptoms. The paper offered recommendations for diagnostic workup and multidisciplinary management based on scientific evidence where available, and on practice-based evidence otherwise. It stated that balance capacities can be improved and at least a proportion of falls prevented through treatment tailored to identified underlying mechanisms.
A 1988 report described six families with 26 affected members, all initially referred as children with slowly progressive paraplegia, slightly delayed motor milestones, normal intellect, and no history of perinatal cerebral event. The paper emphasised that recognition of the hereditary nature of the disease through careful history is key to management. A 2015 paper noted that in Caucasian populations, heterozygous Spastin mutations account for the majority of HSP cases (SPG4), with clinical manifestation typically in the third or fourth decade, and that childhood onset is more common in rarer forms such as SPG3a or complicated HSP like SPG11. A 2005 report described childhood onset in two patients with HSP and thin corpus callosum.
No drug treatment for hereditary spastic paraplegia 54 or any other HSP subtype is mentioned in these abstracts. What is missing is any clinical trial data for a pharmacological intervention, any patient stratification by specific genetic mutation for treatment purposes, and any funding for such trials. The management recommendations are based on rehabilitation and symptom control, not on a drug that modifies the disease course.
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 · 2008 · 57 citations
A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23
AbstractBACKGROUND: The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous neurodegenerative disorders in which the cardinal pathologic feature is upper motor neuron degeneration leading to progressive spasticity and weakness of the lower limbs. To date, 14 autosomal recessive HSP loci have been mapped. METHODS: We have identified a large consanguineous Omani family in which an autosomal recessive form of HSP is segregating. The age at onset varied from 6 to 11 years and the course of the disease is progressive with intellectual disability and is associated with seizures in two individuals. To map the chromosomal location of the causative gene we undertook 250K gene chip SNP analyses of all affected individuals assuming that a founder mutation was responsible. RESULTS: All affected individuals shared a 20.4 Mb (3.25 cM) region of homozygosity located on chromosome 16q21-q23.1, defined by SNP markers rs149428 and rs9929635 (peak multipoint lod score of 4.86). Two candidate genes, dynein, cytoplasmic 1, light intermediate chain 2 (DYNC1LI2) and vacuolar protein sorting 4 homolog A (VPS4A), were sequenced but no disease causing mutations were identified. CONCLUSION: We have mapped the chromosomal location of a novel gene responsible for a form of hereditary spastic paraplegia (HSP) (SPG35) and defined its clinical presentation.
Journal of Rehabilitation Medicine · 2017 · 22 citations · open access
Pathophysiology, diagnostic work-up and management of balance impairments and falls in patients with hereditary spastic paraplegia
AbstractINTRODUCTION: Balance impairments are common in patients with hereditary spastic paraplegia and are among the most debilitating symptoms, as they frequently result in falls and fall-related injuries. Several features of hereditary spastic paraplegia contribute to balance impairments and multiple treatment options exist. However, an overview of these underlying mechanisms and their treatment is currently lacking. METHODS: This paper reviews the pathophysiology, diagnostic workup, and management of balance impairments in hereditary spastic paraplegia. Recommendations are based on scientific evidence, when available, and otherwise reflect practice-based evidence supported by clinical experience. CONCLUSION: Through diligent history-taking and clinical examination, followed by multidisciplinary treatment tailored to the identified underlying mechanisms, balance capacities can be improved in patients with hereditary spastic paraplegia and at least a proportion of falls can be prevented.
Journal of Pediatric Orthopaedics · 1988 · 11 citations
Hereditary Spastic Paraplegia
AbstractHereditary spastic paraplegia is a genetically transmitted disease that is usually autosomal dominant. Characterized by a slow progression of spastic paraparesis, it is frequently misdiagnosed as cerebral palsy. Our experience consists of six families with a total of 26 affected members. All initial referrals were children with a slowly progressive paraplegia. Each child was noted to have slightly delayed motor milestones, normal intellect, and no history of perinatal cerebral event. Each child was treated when necessary with appropriate tendon lengthenings. Recognition is the key to management. A careful patient and family history will reveal the hereditary nature of the disease and help develop treatment plans.
Mutation Spectrum and Infantile Manifestation in Hereditary Spastic Paraplegia
AbstractAims: Hereditary spastic paraplegia (HSP) is genetically heterogeneous and clinically characterized by gait impairment because of weakness and spasticity of the lower limbs. In Caucasian populations, heterozygous Spastin mutations account for the majority of patients (SPG4) with predominant clinical manifestation within the third or fourth decade of life. A clinical manifestation during childhood is well known, but more common in less frequent forms such as SPG3a or complicated HSP, for example, SPG11.
Hereditary spastic paraplegia with thin corpus callosum – childhood onset in two patients
AbstractBackground: The hereditary spastic paraplegias (HSPs) are a group of rare disorders with the predominant clinical feature of spastic gait. They are subdivided into pure and complicated forms according to whether the disorder is associated with other neurologic abnormalities. Autosomal dominant, recessive and X-linked forms of HSP have been defined.
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.
