DeCure for LAMB2-related infantile-onset nephrotic syndrome
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for LAMB2-related infantile-onset nephrotic syndrome — 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 moduleLAMB2-related infantile-onset nephrotic syndrome 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 lamb2-related infantile-onset nephrotic syndrome 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 a European cohort of 89 children from 80 families with nephrotic syndrome presenting in the first year of life, mutations in LAMB2 accounted for 2.5% of families. Across all four genes tested (NPHS1, NPHS2, WT1, LAMB2), 66.3% of families had a detectable mutation. Among 45 children who received steroid treatment, only one had a lasting response, and none of the 28 treated children who carried a causative mutation responded. The authors concluded that infants with mutations in any of these four genes do not respond to steroids.
A Polish study of 33 children with steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis, with onset before age 13, found no pathogenic LAMB2 mutations. Seven of the 33 patients (21%) had mutations in NPHS2 or WT1. The authors suggested that in this population, NPHS2 and WT1 analysis should come first.
A case series from India described four infants with congenital nephrotic syndrome, aged 14 to 60 days, who had genetic mutations including LAMB2. None of the four responded to enalapril, despite anecdotal reports of response in NPHS1 mutations. The authors noted that management in developing countries is largely supportive and that mortality in infancy is high.
What is missing is a treatment that reliably alters the course of LAMB2-related nephrotic syndrome. No drug has been shown to work in these patients. The evidence consists of small case series and genetic surveys; no trial has tested a repurposed agent specifically in LAMB2-mutation carriers. Patient stratification by exact mutation type and funding for a prospective trial would be needed before any drug could be assessed.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PEDIATRICS · 2007 · 442 citations
Nephrotic Syndrome in the First Year of Life: Two Thirds of Cases Are Caused by Mutations in 4 Genes (<i>NPHS1</i>, <i>NPHS2</i>, <i>WT1</i>, and <i>LAMB2</i>)
AbstractOBJECTIVES: Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations. METHODS: We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage. RESULTS: We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment. CONCLUSIONS: First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.
Bosnian Journal of Basic Medical Sciences · 2015 · 22 citations · open access
Retrospective mutational analysis of NPHS1, NPHS2, WT1 and LAMB2 in children with steroid-resistant focal segmental glomerulosclerosis – a single-centre experience
AbstractThe aim of our study was to examine NPHS1, NPHS2, WT1 and LAMB2 mutations, previously reported in two thirds of patients with nephrotic syndrome with onset before the age of one year old. Genomic DNA samples from Polish children (n=33) with Steroid-Resistant Nephrotic Syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS), manifesting before the age of 13 years old, underwent retrospective analysis of NPHS1, NPHS2, WT1 (exons 8, 9 and adjacent exon/intron boundaries) and LAMB2. No pathogenic NPHS1 or LAMB2 mutations were found in our FSGS cohort. SRNS-causing mutations of NPHS2 and WT1 were detected in 7 of 33 patients (21%), including those with nephrotic syndrome manifesting before one year old: five of seven patients. Four patients had homozygous c.413G>A (p.Arg138Gln) NPHS2 mutations; one subject was homozygous for c.868G>A (p.Val290Met) NPHS2. A phenotypic female had C>T transition at position +4 of the WT1 intron 9 (c.1432+4C>T) splice-donor site, and another phenotypic female was heterozygous for G>A transition at position +5 (c.1432+5G>A). Genotyping revealed a female genotypic gender (46, XX) for the first subject and male (46, XY) for the latter. In addition, one patient was heterozygous for c.104dup (p.Arg36Profs*34) NPHS2; two patients carried a c.686G>A (p.Arg229Gln) NPHS2 non-neutral variant. Results indicate possible clustering of causative NPHS2 mutations in FSGS-proven SRNS with onset before age one year old, and provide additional evidence that patients with childhood steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis should first undergo analysis of NPHS2 coding sequence and WT1 exons 8 and 9 and surrounding exon/intron boundary sequences, followed by gender genotyping.
Saudi Journal of Kidney Diseases and Transplantation · 2023 · 1 citations · open access
Genetic Studies in Infants with Congenital Nephrotic Syndrome: A Case Series
AbstractInformation on the genetic profile of congenital nephrotic syndrome (CNS) from India is scarce. The management of CNS is largely supportive of the setting of developing countries, mainly via the administration of intravenous albumin infusions, angiotensin-converting enzyme inhibitors, and levothyroxine. Inadequate infrastructure and management facilities, including genetic analyses, further hamper the outcome. These infants may progress to end-stage renal disease, and mortality is high in infancy. Here, we report a case series of four infants (aged 14-60 days) with CNS from our center with genetic mutations (including mutations in the NPHS1 and LAMB2 genes) that were not described in previous reports from India. Although responsiveness to enalapril has been documented in anecdotal reports of NPHS1 mutations, our case series of four infants did not exhibit any response to enalapril. Our case series adds to the existing literature regarding the genetic profile of CNS in India.
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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