DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hereditary spastic paraplegia 72 — 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 72 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 72 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
A 2009 review notes that hereditary spastic paraplegias are clinically and genetically heterogeneous neurodegenerative disorders, with 35 loci mapped and 17 disease-associated genes identified by that time. SPG4 and SPG7 are the common subtypes in autosomal dominant and autosomal recessive forms, respectively. The review discusses spastin (SPG4) and paraplegin (SPG7), both AAA ATPases. A 2000 study of a family with pure autosomal dominant spastic paraplegia found a novel SPG4 mutation affecting the consensus donor splice site of intron 16, resulting in a premature termination codon at amino acid 578. The mutation segregated with disease in six patients, and the family showed marked intrafamilial variability in age at onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55. A 2024 review of SPG4 states it is the most common type of autosomally inherited spastic paraplegia, with main clinical features limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation. It notes a high degree of clinical heterogeneity, with the same pathogenic variant producing different ages of onset and severity among different patients and even within the same family, and that systematic research on genotype-phenotype correlation is lacking.
A 2006 report describes a novel phenotype of complicated autosomal recessive hereditary spastic paraplegia caused by a new homozygous SPG7 mutation in a family of Turkish descent, with vertical eye movement paresis (Parinaud's syndrome). The paper states that SPG7 mutations account for less than 5% of autosomal recessive hereditary spastic paraplegia families. A 2017 case report describes a spastic paraplegia type 7 patient with an expanded phenotype diagnosed after discovery of pathogenic variants in SPG7. A 2017 review on balance impairments in hereditary spastic paraplegia concludes that through diligent history-taking and clinical examination, followed by multidisciplinary treatment tailored to identified underlying mechanisms, balance capacities can be improved and at least a proportion of falls prevented. The recommendations are based on scientific evidence when available and otherwise reflect practice-based evidence supported by clinical experience.
No drug treatment is mentioned in any of these abstracts. The 2024 SPG4 review explicitly states that the pathogenic mechanism has remained controversial and that systematic research on genotype-phenotype correlation is lacking. The 2009 review notes the heterogeneity of the disorders and the limited number of genes identified at that time. What is still missing is systematic genotype-phenotype correlation studies, a clear pathogenic mechanism for SPG4, and any controlled trial data for pharmacological interventions. Patient stratification by genetic subtype and clinical presentation remains incomplete, and funding for such stratified natural history studies and mechanism-based drug discovery is not described.
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 · 2000 · 48 citations
Intrafamilial variability in hereditary spastic paraplegia associated with an <i>SPG4</i> gene mutation
AbstractThe authors studied a family with pure autosomal dominant spastic paraplegia (ADHSP) that showed a marked intrafamilial variability in both age at onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55. They found a novel mutation in the SPG4 gene, which segregates with the disease in six patients. The mutation affects the consensus donor splice site of SPG4 intron 16, resulting in a premature termination codon at amino acid 578. The data confirm the pathologic significance of SPG4 mutations in pure ADHSP and add to the list of known SPG4 allelic variants.
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 .
AbstractThe hereditary spastic paraplegias (HSPs or SPGs) are clinically and genetically highly heterogeneous neurodegenerative disorders mainly characterized by progressive spasticity and weakness in the lower limbs. The inheritance mode includes autosomal dominant(AD-HSP), autosomal recessive(AR-HSP) and X-linked recessive(XR-HSP). Thirty-five loci have been mapped with 17 disease-associated genes identified. SPG4 and SPG7 are the common subtypes in the AD-HSP and AR-HSP, respectively. The authors briefly review the function of spastin (SPG4) and paraplegin (SPG7), both of which belong to AAA ATPases family, and the recent progress of the study on the pathogenesis of HSPs.
[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.
Complicated autosomal recessive hereditary spastic paraplegia with vertical eye movement paresis (Parinaud's syndrome): a novel phenotype caused by a new homozygous SPG7 gene mutation
AbstractAims: Hereditary spastic paraplegia (HSP) is a clinically and gentically heterogenous neurodegenerative disorder. Clinically an uncomplicated and a complicated form can be distinguished. The uncomplicated form is characterised by slow progressive spastic paraparesis and disturbation of micturition. For the complicated forms a huge number of additional symptoms have been reported. So far thirty-one different genetic loci (SPG1–31) are known. SPG7 encodes the protein paraplegin, which is a mitochondrial metalloprotease. Mutations of SPG7 account for less than 5% of autosomal recessive hereditary spastic paraplegia (ARHSP) families. We report a novel phenotype of complicated ARHSP caused by a new homozygous SPG7 mutation in a family of Turkish decent.
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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