DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 35 — 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 35 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 35 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.
What the evidence adds up to
Hereditary spastic paraplegia 35 (SPG35) was first mapped in 2008 to a 20.4 Mb region on chromosome 16q21-q23.1 in a large consanguineous Omani family. The age at onset in that family ranged from 6 to 11 years, the disease was progressive, and intellectual disability was present; two affected individuals also had seizures. Two candidate genes in the interval, DYNC1LI2 and VPS4A, were sequenced but no disease-causing mutations were found. The causative gene for SPG35 therefore remained unidentified at that time.
The broader hereditary spastic paraplegias are genetically heterogeneous, with at least 20 genes involved by 2003. A separate locus for autosomal recessive HSP with thin corpus callosum and epilepsy was mapped to chromosome 8p12-p11.21 in 2006, with a combined lod score of 7.077. That locus is distinct from SPG35. In 2005, two patients with childhood-onset HSP and thin corpus callosum were described, but no genotype was reported for those cases.
No disease-modifying therapy exists for any form of hereditary spastic paraplegia as of 2019. Treatment remains symptomatic. A 2017 review of balance impairments in HSP recommended multidisciplinary treatment tailored to identified underlying mechanisms, but the evidence base was limited and many recommendations reflected practice-based experience rather than controlled trials. A 2019 critical review of biomarkers for HSP found that 68 of 72 studies had fewer than 50 patients. Diffusion tensor imaging showed the most promise as a biomarker for disease severity, but no biomarker had been validated longitudinally or as a surrogate for neurodegeneration.
What is still missing for SPG35 specifically is the identification of the causative gene, which would be a prerequisite for any targeted therapy. More broadly, the field lacks sensitive, validated biomarkers that can measure treatment effect in small, slow-progressing patient populations. The genetic and clinical heterogeneity of HSP means that any trial would need careful patient stratification, and the rarity of each subtype makes recruitment difficult without multi-centre collaboration and sustained funding.
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 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 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.
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.
