DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 18 — 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 moduleHereditary spastic paraplegia 18 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 hereditary spastic paraplegia 18 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
ER lipid raft associated 2 (ERLIN2) — ERLIN2 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9O9U · 3.0 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Hereditary spastic paraplegia 18 (SPG35) is one of at least 20 genetically distinct forms of hereditary spastic paraplegia, a group of neurodegenerative conditions defined by progressive lower limb spastic paralysis due to corticospinal tract degeneration. The condition is characterised by extreme genetic heterogeneity. In 2008, a large consanguineous Omani family was studied in which an autosomal recessive form of HSP segregated. 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 on chromosome 16q21-q23.1 was mapped, with a peak multipoint lod score of 4.86. Two candidate genes in that region, DYNC1LI2 and VPS4A, were sequenced but no disease-causing mutations were identified. The gene responsible for SPG35 was therefore not found in that study.
A 2019 critical review of biomarkers for hereditary spastic paraplegia identified 72 papers, of which 68 had fewer than 50 patients. All potential biomarkers reviewed could differentiate HSP patients from controls, but only diffusion tensor imaging parameters showed significant correlation with disease severity. The review noted that there is no disease-modifying therapy for HSP and that sensitive biomarkers to measure treatment efficacy in clinical drug trials are lacking. Challenges include the rarity of HSP, its clinical and genetic heterogeneity, and slow disease progression.
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. Treatment was limited to tendon lengthenings when necessary. A 2003 review noted that until recently no functional overlap was apparent in the molecular pathological mechanisms of the hereditary spastic paraplegias, but common themes were beginning to emerge as more genes were identified.
What is still missing for SPG35 specifically is identification of the causative gene, which has not been found since the locus was mapped in 2008. More broadly for HSP, there are no validated biomarkers that can serve as surrogate endpoints in trials, no disease-modifying treatments, and insufficient longitudinal data to assess whether candidate biomarkers reflect underlying neurodegeneration or clinical severity. Patient numbers remain small, and the genetic and clinical heterogeneity of HSP complicates trial design and stratification.
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 Medical Genetics · 2003 · 168 citations · open access
Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias: Table 1
AbstractThe hereditary spastic paraplegias are a group of neurodegenerative conditions that all share the principal clinical feature of progressive lower limb spastic paralysis, caused by either failure of development or progressive degeneration of the corticospinal tract. The conditions are characterised by extreme genetic heterogeneity, with at least 20 genes involved. Until recently, no functional overlap was apparent in the associated molecular pathological mechanisms. However, with recent progress in hereditary spastic paraplegia gene identification, common pathological themes are now emerging.
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 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.
Journal of Neurology Neurosurgery & Psychiatry · 2019 · 0 citations · open access
046 A critical review of biomarkers for hereditary spastic paraplegia
AbstractIntroduction Hereditary spastic paraplegia (HSP) is a rare neurodegenerative condition characterised by lower limb weakness and spasticity. Currently, treatment is symptomatic and there is no disease modifying therapy. Though candidate therapeutic agents have been identified, sensitive biomarkers to measure treatment efficacy in clinical drug trials are lacking. There are many challenges in the search for appropriate biomarkers including the rarity of HSP, clinical and genetic heterogeneity of HSP and slow disease progression. Methods We performed a search on PubMed and Medline using the search terms (‘hereditary spastic paraplegia’ OR ‘spastic paraparesis’) AND ‘biomarker*’. We searched the reference lists of relevant articles to identify further studies. We collected data on number of participants, HSP genotype, methodology, and outcomes. Results 72 papers were identified: 2 on Rating scales, 9 on gait analysis, 33 on neurophysiological measures, 23 on neuroimaging markers and 5 on biochemical markers. The studies reviewed demonstrated variation in methodologies and outcomes, including mixed genotype (41/72 papers) and genotype-specific (31/72 papers) patient cohorts, varied neurophysiological techniques and different outcome measures. 68/72 studies reviewed had small patient numbers (<50 patients). All potential biomarkers reviewed were able to differentiate HSP patients from controls. Only diffusion tensor imaging (DTI) parameters showed significant correlation with disease severity. Conclusion Although useful as diagnostic biomarkers, further studies are required to evaluate these potential biomarkers longitudinally and to assess their reliability as surrogates for underlying neurodegenerative changes and clinical disease severity. DTI showed the most promise as a biomarker for disease severity in HSP.
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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