DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for nephrotic syndrome, type 2 — 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 moduleNephrotic syndrome, type 2 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 nephrotic syndrome, type 2 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.
What the evidence adds up to
In 2002, NPHS2 mutations were found in 12 of 26 multiplex families (46%) and in 7 of 25 single patients (28%) with a clinical diagnosis of steroid-resistant nephrotic syndrome. Five novel mutations were reported: A284V, R196P, V290M, IVS4-1G→T, and 460-467insT. The authors argued that mutational analysis might save some patients from unnecessary steroid treatment and permit prediction of absence of disease recurrence after kidney transplantation. A 2014 case report described a girl with onset at age seven years who had nephrotic proteinuria that failed to decrease after standard steroid therapy; renal biopsy showed focal and segmental glomerulosclerosis. Cyclosporine therapy produced no remission, and chronic renal failure developed. Molecular analysis revealed a homozygous nucleotide substitution in intron 3-4 (c.451+3A>T) not previously reported. The effect on podocin protein was demonstrated by renal biopsy RNA extraction and cDNA amplification, a technique the authors said had never been applied to an NPHS2 mutation. Based on these results, immunosuppressive drugs were discontinued and conservative therapy was undertaken.
A 2019 case report described a 52-year-old man with Waldenström’s macroglobulinemia who presented with nephrotic syndrome features, elevated interleukin-6 and vascular endothelial growth factor, capillary pseudothrombus accumulation, minimal change nephrotic syndrome, and chronic kidney disease. Treatment directed at the macroglobulinemia with bortezomib, thalidomide, and dexamethasone decreased serum immunoglobulin M, and the patient’s proteinuria and serum creatinine improved. The authors noted that renal complications in Waldenström’s macroglobulinemia are rare and most commonly present as mild proteinuria and microscopic haematuria. A 2007 review of nephrotic syndrome complications in children stated that the majority have minimal change disease, and that morbidity and occasional mortality arise from inadequate management and complications, not renal failure.
No drug is repurposed for nephrotic syndrome type 2 in these abstracts. The NPHS2 mutation data are from 2002 and 2014, with no subsequent trial of any agent in mutation-positive patients. The 2019 case involves a different disease (Waldenström’s macroglobulinemia) and a different renal lesion (minimal change with pseudothrombi). What is missing is any prospective trial testing a specific drug in patients with NPHS2 mutations, any systematic attempt to stratify patients by mutation type before treatment, and the funding to conduct such a trial.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of the American Society of Nephrology · 2002 · 248 citations · open access
Novel Mutations in NPHS2 Detected in Both Familial and Sporadic Steroid-Resistant Nephrotic Syndrome
AbstractAutosomal recessive steroid-resistant nephrotic syndrome (SRINS) belongs to the heterogeneous group of familial nephrotic syndrome and represents a frequent cause of end-stage renal disease in childhood. This kidney disorder is characterized by early onset of proteinuria, progression to end-stage renal disease, and histologic findings of focal segmental glomerulosclerosis, minimal change nephrotic syndrome, or both. A causative gene, NPHS2, has been mapped to chromosome 1q25-q31 and was recently identified by positional cloning. This study reports five novel NPHS2 mutations: A284V, R196P, V290M, IVS4-1G-->T, and 460-467insT in 12 (46%) of 26 multiplex families and in 7 (28%) of 25 single patients with the clinical diagnosis of a SRINS. Because NPHS2 mutations were found in nearly 30% of these patients with "sporadic" SRINS, mutational analysis should also be performed in these patients. Besides better classification of the disease entity, identification of NPHS2 mutations may save some of these patients from unnecessary steroid treatment and also permit the prediction of absence of disease recurrence after kidney transplantation.
World Journal of Clinical Cases · 2019 · 4 citations · open access
Pseudothrombus deposition accompanied with minimal change nephrotic syndrome and chronic kidney disease in a patient with Waldenström's macroglobulinemia: A case report
AbstractBACKGROUND: Waldenström's macroglobulinemia (WM) is a rare lymphoid neoplasia, which can have renal complications. These rarely occur, and most common renal manifestations are mild proteinuria and microscopic hematuria. Herein we describe a case of WM that presented with pseudothrombi depositing in capillaries associated with minimal change nephrotic syndrome and chronic kidney disease (CKD). CASE SUMMARY: A 52-year-old man presented with features suggesting nephrotic syndrome. Extensive workups were done, and there were elevated serum levels of interleukin-6 and vascular endothelial growth factor (VEGF), capillary pseudothrombus accumulation associated with minimal change nephrotic syndrome, CKD, and WM. Treatment was directed at the patient's WM with bortezomib, thalidomide, and dexamethasone whereby serum immunoglobulin M (IgM) decreased. The damage of IgM on the kidney was corrected; thus, the patient's proteinuria and serum creatinine had improved. The patient is still under clinical follow-up. CONCLUSION: It is essential for clinicians to promptly pay more attention to patients presenting with features of nephrotic syndrome and do extensive workups to come up with a proper therapy strategy.
After several years of witchhunting, can calcium-based phosphate binding be released on probation?
Abstract37. Karle SM, Uetz B, Ronner V et al. Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2002; 13: 388–393 38. Oleggini R, Bertelli R, Di Donato A et al. Rare functional variants of podocin (NPHS2) promoter in patients with nephrotic syndrome. Gene Expr 2006; 13: 59–66 39. Van Der Berg J, Weening JJ. Role of the immune system in the pathogenesis of the idiopathic nephrotic syndrome. Clin Sci 2004; 107: 125–136 40. Grimbert P, Audard V, Valancuite A et al. Abnormal RNA processing and altered expression of serine-rich proteins in minimal change nephrotic syndrome. Pediatr Res 2005; 57: 133–137 41. Mansour H, Cheval L, Elalouf JM et al. T-cell transcriptome analysis points up a thymic disorder in idiopathic nephrotic syndrome. Kidney Int 2005; 67: 2168–2177 42. Kimata H, Fujimoto M, Furusho K. Involvement of interleukin (IL)13, but not IL-4, in spontaneous IgE and IgG4 production in nephrotic syndrome. Eur J Immunol 1995; 25: 1497–14501 43. Yap HK, Cheung W, Murugasu B et al. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL13 mRNA expression in relapse. J Am Soc Nephrol 1999; 10: 529–537 44. Kolstad A, Holte H, Fossa A et al. Pneumocystis jirovecii pneumonia in B-cell lymphoma patients treated with the rituximab-CHOEP-14 regimen. Haematologica 2007; 92: 139–140 45. Wong CF, Corbett S, Darroch J et al. Rituximab and refractory ANCA associated vasculitis; is low CD4 count detrimental? Abstract in Renal Association and British Renal Society, Harrogate, UK, May 2006 46. Quartier P, Brethon B, Philippet P et al. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001; 358: 1511–1513 47. Kemper MJ, Moller K, Lugwig K et al. Rituximab in treatment of refractory steroid sensitive nephrotic syndrome (abstract). Pediatr Nephrol 2006; 21: 1528 48. FDA Public Health Advisory. Life-threatening brain infection in patients with Systemic Lupus Erythematosus after Rituxan (Rituximab) treatment 2006 http://www.fda.gov/cder/drug/advisory/rituximab. htm 49. Jillella AP, Dainer PM, Kallab AM et al. Treatment of a patient with end stage renal disease with rituximab: pharmacokinetic evaluation suggests rituximab is not eliminated by haemodialysis. Am J Haematol 2002; 71: 219–222
Saudi Journal of Kidney Diseases and Transplantation · 2014 · 3 citations · open access
mRNA sequencing of a novel NPHS2 intronic mutation in a child with focal and segmental glomerulosclerosis
AbstractThe NPHS2 gene encodes podocin, a membrane protein that acts as the structural scaffold in podocyte foot processes. NPHS2 mutations are associated with steroid-resistant nephrotic syndrome (SRNS), with the pathologic variant being focal and segmental glomerulosclerosis (FSGS), an emerging cause of end-stage renal disease in children. We describe a novel NPHS2 sequence variant in a girl with SRNS. Onset occurred at the age of seven years, with edema, hypo-proteinemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia and nephrotic proteinuria. Renal function was normal and autoimmunity markers were negative. Proteinuria failed to decrease after standard steroid therapy. Renal biopsy showed FSGS. Cyclosporine therapy was instituted, but no remission of proteinuria was achieved and chronic renal failure developed. Molecular analysis of the NPHS2 gene revealed a homozygous nucleotide substitution in position c.451+3A>T in intron 3-4. This nucleotide substitution has not been reported in the literature till date. The effect of the detected substitution on podocin protein was demonstrated by renal biopsy RNA extraction and cDNA amplification analysis. This technique had never been applied to a NPHS2 mutation. Based on these results, immunosuppressive drugs were discontinued and conservative therapy was undertaken.
AbstractNephrotic syndrome is an important chronic disease in children, characterized by minimal change disease in the majority. Untreated nephrotic syndrome may cause numerous complications, such as, infections, hypovolemia, hypercoagulability, hyperlipidemia, anemia, growth and development delays. The morbidity and occasional mortality is from inadequate management and complications and not due to renal failure. Expertise and clinical judgement as well as cooperation of the family are crucial for optimal management and a favorable outcome.
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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