DeCure for Spastic paraplegia 30A, autosomal dominant
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for spastic paraplegia 30A, autosomal dominant — 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 moduleSpastic paraplegia 30A, autosomal dominant 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
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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 spastic paraplegia 30a, autosomal dominant 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
kinesin family member 1A (KIF1A) — KIF1A 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 gtpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8UTS · 2.7 Å · ligand GUANOSINE-5'-TRIPHOSPHATE (GTP). Experimental structure, not a prediction.
What the evidence adds up to
A 2006 study mapped a new autosomal recessive locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy to chromosome 8p12-p11.21 in two consanguineous families. The combined lod score was 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. The interval contains neuregulin and KIF13B as candidate genes. This locus is distinct from SPG11 on chromosome 15, which had previously been linked to HSP with thin corpus callosum.
A 2000 study found a novel mutation in the SPG4 gene in a family with pure autosomal dominant spastic paraplegia. The mutation affects the consensus donor splice site of intron 16, producing a premature termination codon at amino acid 578. Within that family, age at onset and clinical severity varied markedly, from severe congenital presentation to mild involvement after age 55. A 2019 review notes that common autosomal dominant forms include SPG4, SPG3, and SPG31, and common autosomal recessive forms include SPG11, SPG7, and SPG15. About 80 spastic paraplegia genes have been described, with almost 70 identified.
For symptom management, a 2015 retrospective study of nine adult HSP patients who received continuous intrathecal baclofen pump therapy found improvements in rectus femoris spasticity (P=0.04) and gastrocnemius spasticity (P=0.03). All nine reported subjective functional improvement; three of four with pre- and post-pump assessments showed clinically meaningful mobility gains. Side effects were managed with dose titration. A 2019 guideline based on expert consultation and lower-level evidence recommends early physical rehabilitation and ankle-foot orthoses. Oral baclofen is first-line, followed by gabapentin and tizanidine. The guideline states that intrathecal baclofen should be considered early if oral drugs fail or cause limiting side effects. It notes that evidence for botulinum toxin in HSP is limited and unclear, and that selective dorsal rhizotomy is not routinely offered and should only be considered for uncomplicated stable HSP when all other treatments have failed.
What is still missing are prospective controlled trials for any drug or intervention in HSP, including for the specific SPG30A form. No trial has stratified patients by genotype. Funding for natural history studies and for trials that separate autosomal dominant from recessive forms is lacking. The evidence for oral medications and botulinum toxin remains weak, and no disease-modifying therapy exists for any HSP 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.
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.
S S Korsakov Journal of Neurology and Psychiatry · 2019 · 5 citations
Common forms of hereditary spastic paraplegias
AbstractA group of hereditary spastic paraplegias includes about 80 spastic paraplegia genes (SPG): forms with identified (almost 70) or only mapped (about 10) genes. Methods of next generation sequencing (NGS), along with new SPG discovering, modify knowledge about earlier delineated SPG. Clinical and genetic characteristics of common autosomal dominant (SPG4, SPG3, SPG31) and autosomal recessive (SPG11, SPG7, SPG15) forms are presented.
Fortschritte der Neurologie · Psychiatrie · 1991 · 4 citations
Familiäre spastische Spinalparalyse - Klinisches Spektrum und differentialdiagnostische Erwägungen
AbstractThe familial spastic paraplegia is a rare disorder of the cerebral nervous system characterized by a slowly progressive spasticity of the lower limbs with early or late onset. There are pure and complicated forms. The disease is inherited by an autosomal dominant mode and a recessive one. In this study 6 patients out of 5 families are presented. The clinical variety, genetic aspects, electrophysiological results and differential diagnosis are discussed.
Use of continuous intrathecal baclofen in hereditary spastic paraplegia
AbstractObjective: Hereditary spastic paraplegia (HSP) is a rare progressive disorder with few treatment options. We aim to describe the effect of continuous intrathecal baclofen (ITB) pump therapy on the clinical and functional outcomes of patients with HSP. Methods: This is a retrospective study, using medical record audit data. Adult patients with HSP who had received ITB trial or therapy and had pre- and post-ITB assessment data available were eligible for inclusion. A purposefully designed audit tool was used. Patients with a successful trial received an ITB implantable SynchroMed ® II pump. Demographic, clinical, and outcome data were obtained pre- and post-pump trial and pump insertion. Functional, spasticity, and mobility measures were compared pre- and post-ITB trial and pre- and post-ITB pump insertion. Results: Data for nine patients were available. Six were male and the median age was 55 years (Q1, Q3: 46, 55). All received an ITB trial, and those who responded favorably (n=8) had an ITB pump inserted. Following ITB therapy, improvements were demonstrated for rectus femoris ( P =0.04) and gastrocnemius spasticity measures ( P =0.03). All patients reported subjective improvements in function, and three of the four with pre- and post-pump assessments, demonstrated clinically meaningful improvements in mobility. Side effects were minimized with appropriate dose titrations. Conclusion: This is the largest retrospective patient study in the field. The potential benefits of ITB in selected patients with HSP were demonstrated. Keywords: baclofen, intrathecal baclofen, hereditary spastic paraplegia, gait analysis
GP116 Approach to managing spasticity in hereditary spastic paraplegia
Abstract<h3>Aim</h3> We aim to provide a guidance in the management of spasticity in children with Hereditary Spastic Paraplegia (HSP). <h3>Introduction</h3> Hereditary spastic paraplegia is a group of clinically and genetically diverse disorders that result in progressive and generally severe lower extremity weakness and spasticity. Spinal and brain MRI and exome sequencing are the most useful investigations for diagnosing HSP. There is a lack of evidence base and guidance for the use of anti-spasticity drugs and uncertainty about the place of other modalities such as intrathecal baclofen (ITB), selective dorsal Rhizotomy (SDR) and botulinum toxin in HSP. <h3>Method</h3> A guideline was prepared based on consultation with experts and regional specialist practice (Level D Evidence) supported by Level A-C evidence for individual treatment options. The guideline includes mode of action, dosage suggestions, side effect profile and cautions for the treatment modalities and summarises key management steps in a flow chart. <h3>Management of spasticity</h3> Management of spasticity in HSP is based on identifying clear and realistic goals in the following three areas: improving mobility, increasing range of motion and relieving spasticity. These goals can be achieved through a combination of physiotherapy, medical agents and, occasionally, surgery. An early and regular physical rehabilitation program is recommended with use of assistive devices such as ankle-foot orthoses. As a first step, a trial of Dopamine should be considered if the diagnosis of HSP is in doubt. Furthermore some forms of HSP have shown response to Dopamine. Oral Baclofen is used as a first-line anti-spasticity drug followed by oral Gabapentin and Tizanidine. Intrathecal baclofen in selected patients has shown promising results; this should be considered early in eligible patients if oral medication is failing to achieve desired spasticity control or side effects limit oral dosing. The evidence for the use of botulinum toxin in HSP is limited and unclear. Its benefits are greatest when combined with therapy and splinting. Diazepam can be used as an adjunct to other oral medications to improve symptom control. Selective Dorsal Rhizotomy is not routinely offered for HSP and should only be considered for uncomplicated stable HSP when all other treatments have failed and quality of life is severely affected. <h3>Conclusion</h3> Managing spasticity well in patients with HSP can immensely improve their quality of life. We propose a standardised referral and management pathway that summarises the approach to medical and surgical options for patients with 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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