DeCure for Dopa-responsive dystonia due to sepiapterin reductase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for dopa-responsive dystonia due to sepiapterin reductase deficiency — 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 moduleDopa-responsive dystonia due to sepiapterin reductase deficiency 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 dopa-responsive dystonia due to sepiapterin reductase deficiency 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
sepiapterin reductase (SPR) — SPR 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 napdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6I6V · 1.43 Å · ligand NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NAP). Experimental structure, not a prediction.
What the evidence adds up to
In a series of 64 index patients with dopa-responsive dystonia whose dystonia improved by at least 50% after L-Dopa treatment, 57 were classified as pure DRD and seven as DRD-plus syndromes. Screening of GCH1, TH, SPR, PTS, PCBD, QDPR, and PARK2 genes found 34 different heterozygous point mutations in 40 patients and six different large deletions in seven patients in GCH1. Among the 17 patients negative for GCH1 mutations, three had mutations in TH, two in SPR, and one in PARK2. No mutations were found in the three BH4 biosynthesis and recycling genes. Patients with TH and SPR mutations had more complex presentations including mental retardation, oculogyric crises, and parkinsonism, and were all classified as DRD-plus. The patient with a PARK2 mutation had pure DRD with good L-Dopa response.
Sepiapterin reductase deficiency is an extremely rare but treatable neurotransmitter disease caused by an enzyme defect in the final step of BH4 synthesis. Unlike other BH4-deficient dopa-responsive dystonias, SRD does not manifest hyperphenylalaninemia and therefore is not detected by newborn screening. Diagnosis may be compromised in mild phenotypes due to variable presenting features and the need for sensitive CSF analysis. A 2019 report describes a leaky splicing variant in SRD.
A 2021 expert review notes that although termed DRD, a subset of patients responds poorly to L-Dopa, regularly observed in severe cases of tyrosine hydroxylase deficiency. The review discusses ongoing efforts to develop novel therapeutics for THD, including mathematical modelling of catecholamine synthesis to improve genotype-to-phenotype predictions and in silico testing of treatment strategies. The authors state there is an urgent demand for more adequate or personalised treatment options for these patients.
What remains missing are prospective trials that stratify patients by genotype, particularly for the rarer TH and SPR mutations where L-Dopa response is often poor. The diagnostic therapeutic trial of L-Dopa in children with dystonia, though advocated for decades, carries risks that are not well quantified in the literature. No randomised controlled data exist to guide treatment selection for SRD or THD beyond case series and expert opinion.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2009 · 147 citations
Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia
AbstractDopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.
Journal of Personalized Medicine · 2021 · 24 citations · open access
Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
AbstractDopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.
Neurology Genetics · 2019 · 13 citations · open access
Leaky splicing variant in sepiapterin reductase deficiency
AbstractSepiapterin reductase deficiency (SRD), an extremely rare but treatable neurotransmitter disease, is an enzyme defect in the final step of tetrahydrobiopterin (BH4) synthesis.1 Unlike other forms of BH4-deficient dopa-responsive dystonia, SRD uniquely does not manifest hyperphenylalaninemia and thus slips through detection by newborn screening. Owing to its variable presenting features and need for a sensitive method of CSF analysis, diagnosis of SRD may be compromised in mild phenotypes.2
Child Neurology: A young child with an undiagnosed case of dystonia responsive to <scp>l</scp> -dopa
AbstractChildhood-onset dystonias are a heterogeneously diverse group. There exists a specific set of dystonias that respond profoundly well to low doses of l-dopa (dopa-responsive dystonia [DRD]). Classical DRD is caused by deficiency of GTP cyclohydrolase 1 or tyrosine hydroxylase, but other conditions can cause dystonias that are partially responsive to dopamine. The idea of a diagnostic therapeutic trial with l-dopa for children who present with dystonia has been around for decades and is frequently advocated for; however, l-dopa trials are not without risk.
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.
