DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 42 — 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 42 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 42 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
solute carrier family 33 member 1 (SLC33A1) — SLC33A1 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 gdsdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9MUN · 3.26 Å · ligand OXIDIZED GLUTATHIONE DISULFIDE (GDS). Experimental structure, not a prediction.
What the evidence adds up to
Hereditary spastic paraplegia 42 is one of many genetically distinct forms of a group of neurodegenerative conditions defined by progressive lower limb spastic paralysis due to corticospinal tract degeneration. More than 20 genes are involved, and until the mid-2000s no functional overlap was apparent among them. In one large consanguineous Omani family, a novel autosomal recessive locus for hereditary spastic paraplegia (designated SPG35) was mapped to chromosome 16q21-q23.1, a 20.4 Mb region of homozygosity shared by all affected individuals with a peak multipoint lod score of 4.86. Age at onset in that family ranged from 6 to 11 years, the disease was progressive, and intellectual disability and seizures were present in some members. Sequencing of two candidate genes in the interval, DYNC1LI2 and VPS4A, found no disease-causing mutations.
Two other families with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum were linked to a different locus on chromosome 8p12-p11.21, with a combined lod score of 7.077 at marker D8S505. In one of those families all affected individuals had thin corpus callosum and mental retardation; in the other, two of three affected individuals had epilepsy. The neuregulin and KIF13B genes in that interval were noted as functional candidates. A separate report described two patients with childhood-onset hereditary spastic paraplegia and thin corpus callosum, but no genetic locus was identified in that study.
An earlier review from 1988 described six families with 26 affected members, all with autosomal dominant inheritance, slow progression of spastic paraparesis, slightly delayed motor milestones, normal intellect, and no perinatal cerebral event. That report emphasised that recognition depends on careful family history, and that the condition is frequently misdiagnosed as cerebral palsy. No treatment beyond appropriate tendon lengthenings was discussed.
What remains missing for hereditary spastic paraplegia 42 specifically is the identification of the causative gene at the 16q21-q23.1 locus, as the two sequenced candidates did not harbour mutations. No clinical trials, no tested therapies, and no patient stratification strategies exist for this subtype. Funding for gene discovery and functional studies, as well as the assembly of larger, genetically confirmed patient cohorts, are still needed before any molecular target can be pursued.
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.
A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy
AbstractBACKGROUND: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. METHODS: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. RESULTS: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. CONCLUSION: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.
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.
Ceylon Medical Journal · 2009 · 2 citations · open access
A case of hereditary spastic paraplegia with demyelinating polyneuropathy
AbstractThe hereditary spastic paraplegias are a group of heterogeneous disorders characterised by lower limb spasticity. Although most cases represent a ‘pure' form, variants with additional ‘complicating' features have been documented. We report a patient with hereditary spastic paraplegia (HSP) having a demyelinating form of polyneuropathy which has not been previously associated with this condition Key words: Absent sensory action potentials markedly prolonged distal motor latencies; reduced nerve conduction velocities DOI: 10.4038/cmj.v50i3.1434 Ceylon Medical Journal Vol.50(3) 2005: 128-129
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.
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