DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for alkaptonuria — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAlkaptonuria maps to a 2-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
approvedNitisinoneApproved drug
Structures already discussed alongside alkaptonuria in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
homogentisate 1,2-dioxygenase (HGD) — HGD is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has fe (ii) ion bound in it, shown as sticks.
Loading structure…
helix sheet iidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1EY2 · 2.3 Å · ligand FE (II) ION (FE2). Experimental structure, not a prediction.
What the evidence adds up to
Alkaptonuria is an autosomal recessive disorder of tyrosine metabolism, incidence estimated at 1:250,000 to 1:500,000, caused by deficiency of homogentisate 1,2-dioxygenase. A 2002 study of 58 patients aged 4 to 80 years reported that joint replacement occurred at a mean age of 55 years, renal stones at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Radiographic severity scores began increasing after age 30, with a more rapid increase in men. Twenty-three new HGO mutations were identified. That same study gave two short nitisinone courses: in a 51-year-old woman, urinary homogentisic acid (HGA) fell from 2.9 to 0.13 g per day after 10 days (7 days at 0.7 mg/day, then 3 days at 2.8 mg/day); in a 59-year-old woman, HGA fell from 6.4 to 1.7 g per day after nine days at 0.7 mg/day. Plasma tyrosine rose from about 1.1 mg/dL (60 µmol/L) in both to about 12.8 mg/dL (700 µmol/L) and 23.6 mg/dL (1300 µmol/L) respectively, with no reported clinical signs or symptoms.
A later longitudinal survey from the National Alkaptonuria Centre in Liverpool, using 2 mg nitisinone off-license, reported that mean baseline urinary HGA of 20,557 µmol/24 h fell by 95.4% at six months, 94.8% at one year, and 94.1% at two years. Serum HGA fell by 83.2% from baseline. Serum tyrosine rose from normal adult reference interval to a mean of 594 ± 184 µmol/L at two years, and urinary tyrosine excretion increased from 103 ± 81 µmol/24 h at baseline to 1071 ± 726 µmol/24 h at two years. These data demonstrate sustained biochemical effect of nitisinone on the tyrosine metabolite profile, but the survey did not report clinical outcomes such as joint pain, ochronosis progression, or need for surgery.
Two 2016 review articles note that aside from dark urine, alkaptonuria is relatively asymptomatic in childhood, and that management continues to be symptomatic. One states that specific treatment with nitisinone appears promising, with additional clinical trials being planned. The other mentions that a clinical trial aimed at proving efficacy of nitisinone in AKU was underway. What is still missing is completed, adequately powered randomised controlled trial data that link biochemical reduction of HGA to meaningful clinical endpoints such as delayed joint replacement, reduced pain, or slowed ochronosis. Patient stratification by age, sex, and baseline disease severity has not been prospectively validated, and long-term safety data on sustained hypertyrosinaemia remain limited.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2002 · 656 citations · open access
Natural History of Alkaptonuria
AbstractBACKGROUND: Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria. METHODS: We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. RESULTS: Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol per liter), respectively, with no clinical signs or symptoms. CONCLUSIONS: The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation.
Annals of Clinical Biochemistry International Journal of Laboratory Medicine · 2017 · 45 citations
The effect of nitisinone on homogentisic acid and tyrosine: a two-year survey of patients attending the National Alkaptonuria Centre, Liverpool
AbstractBackground Alkaptonuria is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National Alkaptonuria Centre in Liverpool has been using 2 mg nitisinone (NTBC) off-license for all patients in the United Kingdom with alkaptonuria and monitoring the tyrosine metabolite profiles. Methods Patients with confirmed alkaptonuria are commenced on 2 mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing NTBC. Thereafter, monitoring and clinical assessments are performed annually. Results Urine homogentisic acid concentration decreased from a mean baseline 20,557 µmol/24 h (95th percentile confidence interval 18,446-22,669 µmol/24 h) by on average 95.4% by six months, 94.8% at one year and 94.1% at two year monitoring. A concurrent reduction in serum homogentisic acid concentration of 83.2% compared to baseline was also measured. Serum tyrosine increased from normal adult reference interval to a mean ± SD of 594 ± 184 µmol /L at year-two monitoring with an increased urinary excretion from 103 ± 81 µmol /24 h at baseline to 1071 ± 726 µmol /24 h two years from therapy. Conclusions The data presented represent the first longitudinal survey of NTBC use in an NHS service setting and demonstrate the sustained effect of NTBC on the tyrosine metabolite profile.
Oxford University Press eBooks · 2016 · 4 citations
Alkaptonuria
AbstractAlkaptonuria is an autosomal recessive disorder with an incidence of 1:250,000 to 1:500,000. Aside from urine that darkens, the disease is relatively asymptomatic in childhood. As a result, the diagnosis is often overlooked early in life and not considered in many patients until they begin to manifest symptoms as adults. Features include pigment deposition (ochronosis) on the eyes, ears, and hands; early-onset, progressive arthritis, particularly of the spine and large joints; valvular heart disease; and renal and prostate stones. Management continues to be symptomatic, but specific treatment with nitisinone appears promising with additional clinical trials being planned.
International Journal of Surgery & Surgical Procedures · 2016 · 1 citations · open access
Alkaptonuria and Ochronosis
AbstractAlkaptonuria (AKU) is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. AKU represents an autosomal recessive condition caused by a defect in the enzyme homogentisate 1,2-dioxygenase, which participates in the degradation of tyrosine. As a result, homogentisic acid and its oxide, accumulate in the blood and are excreted in urine in large amounts. The polymer of homogentisc acid called alkapton, impregnates bradotrophic tissues such as cartilage. A clinical trial aimed at proving efficacy of nitisinone in AKU is currently underway.
Indian Journal Of Applied Research · 2022 · 0 citations
ALKAPTONURIAA CASE REPORT
AbstractAlkaptonuria is a rare inborn disease of error in metabolism with autosomal recessive inheritance. This occurs due to mutation of homogentisate 1, 2-dioxygenase which leads to deposition of homogentisic acid in connective tissues resulting in ochronosis. A case report of 56 year old male patient referred to out- patient department for Rheumatological evaluation with complaints of pain and stiffness in the lower back, hip and knee joint for the past 20 years and loss of weight. The patient had brownish black ocular pigmentation. Radiographs of thoracolumbar spine showed intervertebral disc calcication. Based on the clinical and Xray ndings the presumptive diagnosis of Alkaptonuria was made. There is no specic treatment for Alkaptonuria, Vitamin C in the dose of 1g/day is recommended for older children and adults as it hinders the accumulation and deposition of homogentisic acid. Management is mainly advice on low protein diet and this will reduce tyrosine and phenyalanine in the body. Physiotherapy will help to reduce weight and improve posture.
Indian Journal of Rheumatology · 2011 · 0 citations · open access
Rheumatology reviews: July-September 2011
AbstractTwo cases of advanced alkaptonuria (AKU) with co-existing osteoporosis are described. Case 1 developed multiple non-vertebral fragility fractures, while Case 2 developed vertebral fragility fractures, both refractory to bisphosphonates. Difficulties in diagnosing osteoporosis in AKU complicated by extensive calcifying and ossifying spondylosis are discussed. Both patients continued to fracture despite nitisinone therapy for metabolic control of AKU, as well as bisphosphonate antiresorptive therapy for osteoporosis. Subsequently the patients were treated with teriparatide 20 μg subcutaneous injections daily for two years, leading to reduction in fractures soon after commencing therapy in both cases. Markers of bone remodelling P1NP and CTX were stimulated. No complications due hypercalcaemia or calcification were encountered in either case. We conclude that teriparatide is an effective adjunct in the treatment of AKU when bisphosphonates prove ineffective.
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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