DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for cystinuria — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCystinuria maps to a 5-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 cystinuria 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
solute carrier family 7 member 9 (SLC7A9) — SLC7A9 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 argdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6LI9 · 2.3 Å · ligand ARGININE (ARG). Experimental structure, not a prediction.
What the evidence adds up to
In a retrospective chart review of 26 cystinuria patients followed for an average of 38.2 months, only 4 (15%) achieved and maintained a urine cystine concentration below 300 mg/l. Eleven patients (42%) reached that target but then failed at an average of 16 months, though 7 of those 11 regained success at an average of 9.4 months. Five patients (19%) never reached the target, and 6 (23%) did not return for follow-up. Patient self-assessment of compliance was uniformly high regardless of actual results. A separate single-urologist study of 20 patients over 42.5 months found that 11 compliant patients averaged 1.0 surgical event per patient, while 9 noncompliant patients averaged 4.0 events (p <0.05); 73% of compliant patients were stone-free versus 33% of noncompliant.
A 2020 systematic review of 34 publications reported that D-penicillamine showed success in 13 of 14 studies (92%), tiopronin in all 8 studies (100%), and captopril in all 4 studies, though not all captopril results were statistically significant. Tiopronin had fewer side effects (30%) than D-penicillamine (37%), and captopril had the fewest adverse events (one event in nine patients). The review authors concluded that evidence for benefit from additional drug therapy is scarce and that no drug can be preferred over another; the choice should be personalised based on side-effect risk. A 2013 review noted that no new treatments for cystinuria had emerged in the preceding 15–20 years, though a new measurement method called cystine capacity and in vitro compounds that inhibit cystine crystal growth were being tested in animal models.
A 1976 report described one patient successfully treated with D-penicillamine for over 10 years, but noted that maintaining effective treatment in early childhood is difficult for practical reasons. A 2005 genetic study screened two non-type I cystinuria families for mutations in SLC1A5 and found none, excluding that gene as a cause in those families and leaving the possibility that other genes are involved. What remains missing is a reliable way to sustain patient compliance over decades, a clear ranking of drug efficacy from adequately powered trials, and a molecular understanding that might allow genotype-guided therapy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PubMed · 2003 · 60 citations
Durability of the medical management of cystinuria.
AbstractPURPOSE: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney that leads to an abundance of cystine in the urine. This molecule is poorly soluble in urine and it is prone to crystallization and stone formation at concentrations above 300 mg./l. Medical treatment in these patients has incorporated increasing urine volumes, alkalinization and thiol medications that decrease the availability of free cystine in urine. Despite a reasonable prognosis for reduced stone formation we and others have noted difficulties in patients complying with medical management recommendations. Therefore, we evaluated the durability of treatment success in our patients with cystinuria. MATERIALS AND METHODS: A retrospective chart review was performed in all patients with cystinuria referred to the comprehensive kidney stone center at our institution for an 8-year period. Medical therapy, stone recurrence rates, compliance with medications and scheduled followup, and the results of metabolic evaluations via 24-hour urine collections were reviewed. The average concentrations of urinary cystine in initial and followup 24-hour samples were compared in patients compliant and noncompliant with medical treatment. In addition, each patient was mailed a 1-page questionnaire to assess the self-perception of medical compliance. RESULTS: We identified 26 patients with a mean age of 32 years at referral (range 13 to 67) who were followed an average of 38.2 months (range 6 to 83). Females represented 58% of those with cystinuria. Overall compliance with medical recommendations was poor with a short duration of success. Of the 26 patients followed at our stone center only 4 (15%) achieved and maintained therapeutic success, as defined by urine cystine less than 300 mg./l. An additional 11 patients (42%) achieved therapeutic success but subsequently had failure at an average of 16 months (range 6 to 27). Of these patients 7 (64%) regained therapeutic success at an average of 9.4 months (range 4 to 20). Five patients (19%) never achieved therapeutic success, while an additional 6 (23%) failed to present to followup appointments or provide subsequent 24-hour urine studies despite referral to a tertiary care center. Patient self-assessment of medical compliance was uniformly high regardless of physician perceptions or treatment results. CONCLUSIONS The durability of medically treating patients with cystinuria is limited with only a small percent able to achieve and maintain the goal of decreasing cystine below the saturation concentration. Greater physician vigilance in these complicated stone formers is required to achieve successful prophylactic management. Furthermore, these patients require better insight into the own disease to improve compliance.
Current Opinion in Nephrology & Hypertension · 2013 · 51 citations
Update on cystinuria
AbstractPURPOSE OF REVIEW: Cystinuria is a rare genetic disease with increased urinary excretion of the poorly soluble amino acid cystine. It can lead to significant morbidity in affected patients due to the often large and recurrent resulting kidney stones. Treatment is focused on the prevention of stone formation. There have been few advances in the available therapeutic options for the disorder in the last 15-20 years. RECENT FINDINGS: Although no new treatments have emerged in the prevention of cystinuria in recent years, several developments hold promise for advancing the field of caring for affected patients. A new method of measuring urinary cystine and estimating potential for stone formation, called cystine capacity, may prove to be a useful tool in monitoring the disease. The discoveries of the mutations that cause cystinuria have led to a new classification system based on genotype that is more accurate than the prior phenotypic one. The finding of new compounds that inhibit cystine crystal growth in vitro, now being tested in animal models, may lead to new potential therapies in years to come. The Rare Kidney Stone Consortium has developed a registry and hopes to lead further efforts in dealing with cystinuria. SUMMARY: With several recent advances in the monitoring and treatment of cystinuria, and the gathering of clinical patient data, there are now opportunities for new management protocols and therapies.
UROLOGICAL INTERVENTION IN PATIENTS WITH CYSTINURIA IS DECREASED WITH MEDICAL COMPLIANCE
AbstractPURPOSE: Theoretically patients with cystinuria compliant with medical treatment should undergo fewer surgical procedures than those noncompliant with treatment. We describe a single urologist's experience (SYN) with the effects of medical management on the number of surgical interventions required in patients with cystinuria treated at our metabolic stone clinic (MSC). MATERIALS AND METHODS: The records of 20 patients with cystine stones seen at our MSC (mean followup of 42.5 months) were evaluated. The number of surgical interventions (endourology or open surgery) during followup were recorded as surgical events. Patients were placed into a compliant or noncompliant category based on their attendance record at scheduled appointments at our MSC and whether they adhered to the prescribed medical regimen by report. Patients were classified in an active disease category if recent imaging revealed a clinically significant stone burden greater than 3 mm. Statistical analysis of the number of surgical events for stone-free patients compliant with treatment versus noncompliant was conducted (Student's t test). RESULTS: Of the 20 patients 11 were categorized as compliant and 9 as noncompliant. Of the compliant patients the average number of surgical events was 1.0 per patient versus 4.0 in the noncompliant group (p <0.05). Of the 11 compliant patients 8 (73%) were stone-free compared to 3 (33%) in the noncompliant group. CONCLUSIONS: The majority of our patients with cystinuria compliant with treatment underwent a significantly fewer number of surgical procedures per year than those noncompliant with treatment. Active medical management in patients with cystinuria compliant with treatment decreases the incidence of surgical interventions.
AbstractAt the beginning of the four chapters on phenomena, analysis, pathophysiology and therapy of cystinuria the essentials of the published literature are summarized. The frequency of cystinuria is in the order of 1:10,000. Besides the cystine lithiasis occurring in nine tenths of all cystinuria patients neurological diseases may also be observed. All commonly applied methods to analyze cystine detect the sum of cystine and cysteine. Cystinuria is characterized by a higher cystine excretion, up to the 100-fold of the normal. Also the concentrations of lysine, arginine and ornithine in the urine of cystinuria patients are elevated, caused by intestinal and renal transport defects. Inevitable damage of renal parenchyma by multiple operations can drastically be reduced by the therapy with D-penicillamine or alpha-mercaptopropionylglycine. The disadvantages of that formation of soluble asymmetric disulfides are the side effects, such as nausea, gastric difficulties and dermatosis, occurring in up to 50% of the patients. Using the especially developed method with HPLC separation and electrochemical detector with a mercury electrode, cystine and cysteine are analyzed simultaneously. In the urine of healthy persons the molar concentration of cysteine is in the same order as cystine. But in cystinuria the cysteine concentration in urine is about a thousand times less than that of cystine. These results are evidence that a shifted redox-equilibrium of cystine-cysteine is also typical of cystinuria. The molar cysteine percentage of cysteine in healthy persons is increased from 30 to 50% by oral ascorbic acid administration. Therefore a vitamin C therapy for cystinuria is developed. 31 cystinuria patients who receive 5 g of vitamin C a day show a decrease in the cystine concentration of about 40%. Up to now, no side effects have been observed. The most obvious sign of the positive effect of the proposed vitamin C therapy for cystinuria is the missing cystine sediment in fresh urine.
Journal of Inherited Metabolic Disease · 2005 · 9 citations
Search for mutations in <i>SLC1A5</i> (19q13) in cystinuria patients
AbstractTo elucidate whether SLC1A5 is involved in the aetiology of cystinuria, we screened two non-type I cystinuria families without detectable mutations inSLC7A9 (and SLC3A1) but compatible with linkage to 19q13 for genomic variants in SLC1A5. Despite evidence for an involvement of SLC1A5 in the aetiology of cystinuria, we could not identify any mutation in this gene in the two families. With SLC1A5, a further candidate gene for cystinuria can be excluded as being involved in the pathogenesis of this disease in these two families. Of course, there remains the possibility that other genes are involved in cystinuria; further molecular studies will clarify the complex nature of this disorder.
Journal of Paediatrics and Child Health · 1976 · 3 citations
The Long‐Term Management of Cystinuria
AbstractMacdonald, W. B., and Selvarajah, K. (1976). Aust. paediat. J. , 12, 102–112. The long‐term management of cystinuria. The maintenance of effective treatment for cystinuria is difficult in early childhood, for practical reasons. Older children and adults who have had renal colic or surgery are motivated to persist with tedious and inconvenient treatment as part of their life‐style. Experiences with the management of a selected sample of five children with cystinuria are recorded. The group includes one patient who has been successfully treated with D‐penicillamine for over 10 years, one of the longest treatment spans recorded for this drug in the treatment of cystinuria.
Minerva Urologica e Nefrologica · 2020 · 2 citations
The effect of additional drug therapy as metaphylaxis in patients with cystinuria: a systematic review
AbstractINTRODUCTION: To systematically review the effect of additional drug therapy as metaphylaxis in patients with cystinuria. EVIDENCE ACQUISITION: A literature search of three databases (MEDLINE, Embase and the Cochrane Library) was performed according to the PRISMA-guidelines enclosing articles published up to May 2019. A total of 1117 articles were screened. Thirty-four publications met the inclusion criteria for this review. EVIDENCE SYNTHESIS: Male-female ratio in the studied cohorts was 49.9% - 50.1%. The majority of studies showed a positive effect in reducing stone events and/or urinary cystine excretion. D-Penicillamine showed success in 13/14 (92%) studies, whereas Tiopronin-treatment showed a reduction in all (8/8; 100%) studies. All studies on Captopril (4/4) showed a decrease, however not all significant. The same is true for studies on Thiols in combination with Captopril (2/2). Furthermore, Tiopronin showed less side effects compared to D-penicillamine, respectively 30% and 37%. Captopril showed the least adverse events, with one event in nine patients. CONCLUSIONS: The evidence on benefit of additional drug therapy in patients with cystinuria is scarce. All studied medications showed an effect on stone event and urinary cystine excretion, when used in addition to hyperhydration, alkalization and a diet low on methionine. Based on this systematic review, no drug can be preferred over another. An important aspect in the choice of drug is the risk of side effects. Therefore, the choice of additional drug should be personalized for every patient where the risk of side effects should be taken into consideration.
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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