DeCure for Aromatic L-amino acid decarboxylase deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for aromatic L-amino acid decarboxylase 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 moduleAromatic L-amino acid decarboxylase 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
approvedCarbidopaApproved drugapprovedL-DOPAApproved drug
Structures already discussed alongside aromatic l-amino acid decarboxylase deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
X-ray structure of Human holo aromatic L-amino acid decarboxylase (AADC) complex — Carbidopa has a real, experimentally solved structure in complex with this target (PDB 9GNS, 1.93 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet 142drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9GNS · 1.93 Å · ligand Carbidopa (142). Experimental structure, not a prediction.
What the evidence adds up to
A pathogenic S250F missense mutation was introduced into the murine Aadc gene to create a mild model of aromatic L-amino acid decarboxylase deficiency. Homozygous mutant mice were viable and expressed a stable but minimally active AADC protein. Brain dopamine concentrations were only modestly reduced, but serotonin levels were markedly diminished, and behaviour and autonomic function were perturbed. No morphologic abnormalities of dopaminergic cells were found; the striatum and substantia nigra appeared normal, and no loss of dopamine-expressing cells was detected. The authors concluded that even minute levels of active AADC allow substantial dopamine production in this model.
A 26-year-old woman with a mild AADC deficiency phenotype became pregnant naturally. Before pregnancy, treatment with rotigotine, pyridoxine, and escitalopram had produced remarkable improvement in fluctuating muscular weakness, oculogyric crises, palpebral ptosis, balance, and gait. Rotigotine was later replaced by prolonged-release pramipexole (up to 0.78 mg/day), and selegiline was added (up to 7.5 mg/day). During pregnancy, escitalopram was suspended, and doses of pramipexole and selegiline were decreased without obvious neurological worsening. No oculogyric crises or myoclonic jerks were observed; limb rigidity, fatigability, and muscular weakness were well controlled. The UPDRS-part III score did not change. Preeclampsia occurred at 31 weeks. At 38 weeks, caesarean delivery resulted in a live male newborn with low birth weight (2,440 grams) and small for gestational age. The infant had transient tachypnoea and hypoglycaemia on the first day but grew regularly after early artificial nursing, with no significant health problems in the following months. The authors state that fertility may not be impaired in AADC deficiency, that pregnancy can be managed in mild phenotypes, and that low doses of pramipexole and selegiline may have a good efficacy and safety profile during pregnancy.
Gene therapy for AADC deficiency is described as a new strategy. The therapy involves real-time MRI-guided introduction of a copy of the defective DDC gene directly into the substantia nigra and ventral tegmental area. The abstract reports that treated children in the United States recovered very quickly, began to sit up, stand, and attempted to walk. In the first Polish patients treated in 2019, spectacular changes were observed, with children raising their heads soon after the procedure. The abstract states that early accurate diagnosis and prompt gene therapy can minimise the consequences of deficient neurotransmitters.
What is still missing are controlled trials with long-term follow-up, standardised outcome measures, and data on how patient stratification by mutation severity or age at treatment affects response. The mouse model is mild and may not capture severe human disease. The pregnancy report is a single case. Gene therapy reports are early and lack published quantitative results such as survival or motor milestone rates in a defined cohort. Funding for larger, multi-centre studies and for developing accessible screening is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2017 · 15 citations · open access
A pathogenic S250F missense mutation results in a mouse model of mild aromatic l-amino acid decarboxylase (AADC) deficiency
AbstractHomozygous mutations in the aromatic l-amino acid decarboxylase (AADC) gene result in a severe depletion of its namesake protein, triggering a debilitating and often fatal form of infantile Parkinsonism known as AADC deficiency. AADC deficient patients fail to produce normal levels of the monoamine neurotransmitters dopamine and serotonin, and suffer a multi-systemic disorder characterized by movement abnormalities, developmental delay and autonomic dysfunction; an absolute loss of dopamine is generally considered incompatible with life. There is no optimal treatment for AADC deficiency and few truly good models in which to investigate disease mechanisms or develop and refine therapeutic strategies. In this study, we introduced a relatively frequently reported but mildly pathogenic S250F missense mutation into the murine Aadc gene. We show that mutants homozygous for the mutation are viable and express a stable but minimally active form of the AADC protein. Although the low enzymatic activity of the protein resulted in only modestly reduced concentrations of brain dopamine, serotonin levels were markedly diminished, and this perturbed behavior as well as autonomic function in mutant mice. Still, we found no evidence of morphologic abnormalities of the dopaminergic cells in mutant brains. The striatum as well as substantia nigra appeared normal and no loss of dopamine expressing cells in the latter was detected. We conclude that even minute levels of active AADC are sufficient to allow for substantial amounts of dopamine to be produced in model mice harboring the S250F mutation. Such mutants represent a novel, mild model of human AADC deficiency.
Movement Disorders Clinical Practice · 2018 · 7 citations · open access
Successful Pregnancy in a Patient with L‐Amino Acid Decarboxylase Deficiency: Therapeutic Management and Clinical Outcome
AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder of biogenic amine metabolism presenting with developmental delay, hypokinetic movement disorders, hypotonia, and autonomic dysfunctions.1 We report on the successful pregnancy in a previously reported 26-year-old AADC patient with a mild phenotype (Table 1).2 Since the diagnosis at the age of 22, treatment with rotigotine, pyridoxine, and escitalopram resulted in a remarkable improvement of fluctuating muscular weakness, oculogyric crises, palpebral ptosis, balance, and gait.2 After, as consequence of behavioral disinhibition and reduced control of sexual impulses, rotigotine was replaced by a prolonged release formulation of pramipexole (up to 0.78 mg/day once a day). Selegine was added to improve diurnal fluctuation of motor symptoms (up to 7.5 mg/day after a very slow dose increasing). While MAO-inhibitors and SSRIs association is contraindicated in common neuropsychiatric disorders due to the risk of serotonin intoxication syndrome, their synergic effect may be exploited to magnify the residual enzymatic activity in the defect of serotonin synthesis, such as AADC deficiency. Compound heterozygous for the mutations p.Tyr37Thrfs*5 (c.105delC) and p.Phe237Ser (c.710 T>C) The pregnancy of our patient occurred naturally at the age of 26. Escitalopram was suspended to prevent the risk of low birth weight.3 Doses of pramipexole and selegiline could be decreased (Table 1) without obvious neurological worsening. No oculogyric crises or myoclonic jerks were observed, and limb rigidity, fatigability, and muscular weakness were well controlled. UPDRS-part III score did not change with respect the prepregnancy status (Table 1). Blood pressure remained below the normal range for the age. At the 31st week of gestation preeclampsia occurred. At the 38th week of gestation, a cesarean delivery (cardiac deceleration at cardiotocography) resulted in the birth of a vital (Apgar score 91 and 105) low birth weight (2.440 grams) and small (for gestational age) male newborn. The infant presented with transient tachypnea and hypoglycemia in the first day after birth. His growth was regular after the early introduction of artificial nursing. No significant health problems were observed in the following months. Pregnancy was previously reported in inherited neurotransmitter disorders with a less severe phenotype than AADC deficiency (35 women with autosomal dominant guanosine triphosphate cyclohydrolase 1 deficiency, one with dihydropterine reductase deficiency, and one with 6-pyrovoyl-tetrahydrobiopterin synthase deficiency).4, 5 The defect of monoaminergic neurotransmitters in AADC deficiency potentially impairs embryo-maternal interactions at preimplantation stages of early embryogenesis, which could be prevented by the treatment with drugs acting on dopaminergic axis.6 Efficacy and safety profile of pramipexole and selegiline during pregnancy and lactation are reported, in 24 and three women affected by Parkinson disease or restless legs syndrome, respectively.5, 7 Pramipexole was associated with spontaneous abortion in 3 cases (co-exposition with isotretinoin in one case) while selegiline was associated with a ventral septal defect in a twin newborn (co-exposition with L-DOPA/carbidopa and entacapone).5 The present case shows that in AADC deficiency: (a) fertility may be not impaired, (b) the course of pregnancy can be successfully managed in patients with mild phenotypes, and (c) low dosages of pramipexole and selegiline may have a good efficacy and safety profile during pregnancy. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. M.M.: 1A, 1B, 1C, 3A, 3B F.M.: 1B, 1C, 3A L.P.: 1A, 1B, 1C, 3A S.F.: 1A, 1B, 1C, 3A C.C.: 1C, 3B Cl.C.: 1C, 3B G.M.: 1A, 1B, 1C, 3B V.L.: 1A, 1B, 1C, 3A, 3B Ethical Compliance Statement: We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work and that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed written consent was obtained from the patient for the publication of her clinical data. Funding Sources and Conflicts of Interest: None of the authors have anything to declare. Financial Disclosures for previous 12 months: None of the authors have anything to declare.
Pediatria i Medycyna Rodzinna · 2021 · 0 citations · open access
Gene therapy in the treatment of aromatic L -amino acid decarboxylase deficiency
AbstractAromatic L-amino acid decarboxylase deficiency is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants of the DDC gene. The disease manifests already in newborns and infants. The presentation includes neurological symptoms, a significant delay in motor development and oculogyric crisis. Currently, gene therapy is successfully used in the treatment of aromatic L-amino acid decarboxylase deficiency. Until recently, no effective treatment for the disorder was known. The affected children died in the first decades of life. Gene therapy is a new and promising therapeutic strategy. The first genetic therapies for aromatic L-amino acid decarboxylase deficiency were implemented in the United States. The treated children recovered very quickly, began to sit up, stand, and even attempted to walk. For the first time in Europe, this method was used in 2019 in Poland, at the Interventional NeuroTherapy Centre at Bródno Hospital in Warsaw, with the involvement of a team of specialists under the leadership of Professor Mirosław Ząbek and Professor Krzysztof Bankiewicz. The therapy involves a real-time magnetic resonance imaging-guided introduction of a copy of the defective gene directly into the substantia nigra and the ventral tegmental area. Spectacular changes were observed in the first Polish patients treated with this innovative method. The children began to raise their heads soon after the procedure. Early accurate diagnosis and prompt implementation of appropriate treatment can minimise the consequences of deficient neurotransmitters in paediatric patients. This can be achieved with gene therapy, which is a chance for children affected by this rare disease.
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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