DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 4 — screening already-approved drugs against its 6-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 4 maps to a 6-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 4 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
collagen type III alpha 1 chain (COL3A1) — COL3A1 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 flcdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6FZW · 2.78 Å · ligand CITRATE ANION (FLC). Experimental structure, not a prediction.
What the evidence adds up to
Hereditary spastic paraplegia type 4 (SPG4) is the most common autosomal dominant form of hereditary spastic paraplegia. Its main clinical features are limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without nerve atrophy, ataxia, cognitive impairment, seizures, or muscle tone disorders. The SPAST gene is the main pathogenic gene, and various pathogenic SPAST variants have been discovered. A 2023 report describes a 38-year-old woman with an eight-year history of progressive difficulty walking, spastic paraparesis, normal brain and spinal cord MRI, and no family history of similar complaints. Genetic analysis found a novel heterozygous SPAST variant, c.1751A>G p.(Asp584Gly). Four other nucleotide substitutions predicted to affect the same amino acid have been reported previously in adult-onset HSP.
The disease features a high degree of clinical heterogeneity. The same pathogenic variant can produce different ages of onset and severity among different patients and even within the same family. There is a lack of systematic research on the correlation between genotype and phenotype of SPG4, and the pathogenic mechanism remains controversial. A 1988 series of six families with 26 affected members noted that all initial referrals were children with slowly progressive paraplegia, slightly delayed motor milestones, normal intellect, and no history of perinatal cerebral event. Each child was treated when necessary with tendon lengthenings.
Balance impairments are common in patients with hereditary spastic paraplegia and frequently result in falls and fall-related injuries. A 2017 review recommends multidisciplinary treatment tailored to identified underlying mechanisms, stating that balance capacities can be improved and at least a proportion of falls prevented, but these recommendations are based on practice-based evidence supported by clinical experience rather than controlled trials. Other abstracts describe a new locus on chromosome 8p12-p11.21 for autosomal recessive HSP with thin corpus callosum and epilepsy, and an expanded phenotype in a patient with spastic paraplegia type 7, but these do not concern SPG4.
What is still missing is systematic research correlating SPAST genotype with phenotype, a settled understanding of the pathogenic mechanism, and controlled trial evidence for any intervention that improves balance or prevents falls in this specific subtype.
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 · 2006 · 52 citations
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.
Clinical Case Reports · 2017 · 12 citations · open access
Expanded phenotype in a patient with spastic paraplegia 7
AbstractKey Clinical Message Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG 7 .
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.
[Advance of research on Hereditary spastic paraplegia type 4].
AbstractSpastic paraplegia type 4 (SPG4) is the most common type of autosomally inherited spastic paraplegia. Its main clinical features include typical simple hereditary spastic paraplegia, with neurological impairments limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without accompanying features such as nerve atrophy, ataxia, cognitive impairment, seizures, and muscle tone disorders. SPAST is the main pathogenic gene underlying SPG4, and various pathogenic SPAST variants have been discovered. This disease has featured a high degree of clinical heterogeneity, and the same pathogenic variant can have different age of onset and severity among different patients and even within the same family. There is a lack of systematic research on the correlation between the genotype and phenotype of SPG4, and the pathogenic mechanism has remained controversial. This article has provided a review for the clinical characteristics, pathogenic gene characteristics, correlation between the genotype and phenotype, and pathogenic mechanism of this disease, with an aim to provide reference for its clinical diagnosis and treatment.
Case Reports in Genetics · 2023 · 0 citations · open access
A Novel SPAST Variant Associated with Isolated Spastic Paraplegia
AbstractGenetic variants in SPAST are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood. Pathogenic SPAST variants are often observed in isolated cases, likely due to reduced penetrance and clinical variability. We report an isolated case of SPG4 associated with a novel likely pathogenic variant in SPAST. A 38-year-old woman presented with an eight-year history of progressive difficulty walking. Neurological examination revealed spastic paraparesis in the absence of upper motor neuron dysfunction, sensory deficits, or intellectual disability. Magnetic resonance imaging (MRI) of the brain and spinal cord was normal. No family members had similar complaints. Genetic analysis revealed a novel heterozygous sequence variant in SPAST, c.1751A > G p.(Asp584Gly) (NM_014946.4). The affected amino acid is highly conserved among orthologue and paralogue species. Four other nucleotide substitutions predicted to affect the same amino acid, a “hot spot”, have been reported previously in adult-onset HSP. This report describes a novel SPAST variant in a female with HSP without a known family history of the disorder.
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.
