DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 51 — 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 51 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 51 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
adaptor related protein complex 4 subunit epsilon 1 (AP4E1) — AP4E1 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 9U9I · 4.0 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Hereditary spastic paraplegia 51 is one of many genetically distinct forms of a group of neurodegenerative conditions that share progressive lower limb spastic paralysis due to corticospinal tract degeneration. At least 20 genes are involved across the hereditary spastic paraplegias, and no functional overlap in the underlying molecular pathology was apparent until the mid-2000s. The conditions are classified as pure when spasticity occurs in isolation or complicated when other neurological abnormalities are present. A 2006 study of two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia mapped a new locus on chromosome 8p12-p11.21, between markers D8S1820 and D8S532, with a combined lod score of 7.077 at marker D8S505. Affected individuals in one family had thin corpus callosum and mental retardation; in the other family two of three affected individuals had epilepsy. Neuregulin and KIF13B were noted as functional candidate genes within that interval.
In Caucasian populations, heterozygous Spastin mutations (SPG4) account for the majority of HSP patients, with onset typically in the third or fourth decade. Childhood manifestation is more common in less frequent forms such as SPG3a or complicated HSP like SPG11. A 2005 report described childhood onset in two patients with hereditary spastic paraplegia and thin corpus callosum, a complicated subtype that had been linked to chromosome 15q13-q15 (SPG11), though some families were not linked to that locus.
As of 2019, there is no disease-modifying therapy for any form of hereditary spastic paraplegia; treatment remains symptomatic. A critical review of biomarkers identified 72 papers, of which 68 had fewer than 50 patients. All reviewed biomarkers could differentiate HSP patients from controls, but only diffusion tensor imaging parameters showed significant correlation with disease severity. The review concluded that further longitudinal studies are needed to evaluate these potential biomarkers as surrogates for neurodegenerative changes and clinical severity. What is still missing for hereditary spastic paraplegia 51 specifically are any clinical trials, any identified drug candidates, any biomarker validation in that genotype, and any natural history data that could inform trial design or patient 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 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.
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.
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.
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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