DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for spermatogenic failure 26 — 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 moduleSpermatogenic failure 26 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 spermatogenic failure 26 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 43 azoospermic men, testicular sperm from 17 with spermatogenic failure showed a total chromosomal abnormality frequency of 8.2%, not statistically different from the 5.6% seen in 26 men with normal spermatogenesis. Aneuploidy for chromosome 18 was higher in the spermatogenic failure group (3.2% versus 1.3%). Sex chromosome aneuploidy in the spermatogenic failure group was 5.8%, similar to the chromosome 18 rate. The authors concluded that no overall difference in total chromosomal abnormality frequency was observed between the two groups.
Medical therapy for primary spermatogenic failure has been attempted with hormones and antioxidant nutritional supplements, but no treatment has consistently demonstrated efficacy. The 2011 review states that empiric medical therapy has been largely replaced by assisted reproductive techniques, and that idiopathic spermatogenic failure likely results from multiple unidentified defects in sperm production. A 2005 study of 41 azoospermic men found that BOULE transcript levels in testicular tissue were significantly decreased in patients with spermatogenic failure and progressively decreased with increasing severity. Among 31 men who underwent sperm retrieval, those with successful retrieval had significantly higher BOULE transcript levels than those with failed retrieval. Using a cut-off value of 0.5 for the BOULE transcript ratio, the authors reported 100% sensitivity and 100% specificity for predicting successful sperm retrieval.
A 2019 study of 150 infertile men (with oligozoospermia or azoospermia) and 150 fertile controls identified two novel mutations in the KDM3A gene in the infertile group: a transversion point mutation in exon 12 and a single nucleotide deletion in exon 24. No Y chromosome microdeletions were found in these patients. The authors considered these mutations as a possible origin of the men’s unexplained severe spermatogenic failure. A 1988 review of 8879 vasectomies performed by one physician reported 97 failures of all types, including 32 early overt failures (0.60%) and 61 technical failures (1.14%) involving persistence of small numbers of sperm. Four late overt failures (0.08%) were discovered because of a pregnancy occurring at least four years after two azoospermic test results.
What remains missing is a reliable way to identify which patients might benefit from any given treatment, and no therapy has been shown to consistently restore spermatogenesis. The molecular defects underlying most cases of spermatogenic failure are still unknown, and no large-scale, well-controlled trials of medical therapy have been conducted. Patient stratification by genetic or transcript markers such as BOULE or KDM3A mutations has not been prospectively validated in a clinical trial setting.
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 Reproduction · 2002 · 101 citations
FISH analysis of chromosome X, Y and 18 abnormalities in testicular sperm from azoospermic patients
AbstractBACKGROUND: Sperm extracted from testicular biopsies of azoospermic men can successfully be used for ICSI. The concern exists that testicular sperm from azoospermic men suffering from severe testicular failure may have a higher frequency of aneuploidy, which may lead to an increased risk for chromosomally abnormal offspring. METHODS: Testicular sperm from patients showing spermatogenic failure (n = 17) and from patients with normal spermatogenesis (n = 26) were analysed by fluorescence in-situ hybridization (FISH). Numerical chromosomal abnormalities for chromosomes X, Y and 18 were evaluated by FISH in a total of 1697 testicular sperm derived from 43 azoospermic patients. RESULTS: No difference was observed between the frequency of chromosomal abnormalities in testicular sperm from patients with normal spermatogenesis (5.6%) and from patients with spermatogenic failure (8.2%). However, the frequency of aneuploidy for chromosome 18 was higher in the group of azoospermic patients with spermatogenic failure than in the group with normal spermatogenesis (3.2 versus 1.3%). Within the obstructive group, sex chromosome aneuploidy (4.5%) occurred more frequently than chromosome 18 aneuploidy (1.3%; P < 0.001). Among testicular sperm derived from patients with spermatogenic failure, sex chromosomal aneuploidy (5.8%) was similar to that for chromosome 18 (3.2%). CONCLUSIONS: So far, no difference in the total frequency of chromosomal abnormalities has been observed between patients with normal spermatogenesis and patients with severe testicular failure. However, aneuploidy for chromosome 18 was higher in the group with spermatogenic failure.
Asian Journal of Andrology · 2011 · 57 citations · open access
Medical therapy for spermatogenic failure
AbstractMedical treatment of men with primary spermatogenic failure remains largely ineffective in contrast to those with secondary testicular failure. Treatment has been attempted with a multitude of agents ranging from hormones to nutritional supplements (antioxidants). While some studies have demonstrated benefit to some treatments, no treatments have consistently demonstrated efficacy nor has it been possible to reliably identify patients likely to benefit. Idiopathic spermatogenic failure likely results from multiple discrete defects in sperm production that are as yet unidentified. A better understanding of these defects will yield more effective treatment options and appropriate triage of patients to specific therapeutic regimens. This review focuses on the rationale and current evidence for hormonal and antioxidant therapy in medical treatment of male infertility, spermatogenic failure in particular. Although empiric medical therapy for spermatogenic failure has been largely replaced by assisted reproductive techniques, both treatment modalities could play a role, perhaps as combination therapy.
The lurking sperm. A review of failures in 8879 vasectomies performed by one physician
AbstractVasectomy techniques and failure rates vary among surgeons, and the criteria for failure are not often clearly defined. To help establish a yardstick for comparative purposes, a series of 8879 consecutive vasectomies performed with uniform technique over 24 years was reviewed. A subgroup of 5331 men who had returned for at least two postoperative semen tests--the study group--was used for follow-up analysis. Failures were defined as early or late and also were categorized as overt or technical according to the numbers, motility, or persistence of the remaining spermatozoa. There were 97 failures of all types, including 32 (0.60%) early and overt failures and 61 (1.14%) technical failures that involved the persistence of small numbers of spermatozoa, possibly of no significance. Four (0.08%) late overt failures were also seen; each of these was discovered as a result of a pregnancy, and each occurred at least four years after two azoospermic test results. Of the 97 failures, four were recognized as due to missed vasa deferentia, and the remainder were attributed to recanalization. Whether improved and reproducible failure rates can be consistently obtained by other techniques is not yet clear.
Messenger RNA transcripts of the meiotic regulator BOULE in the testis of azoospermic men and their application in predicting the success of sperm retrieval
AbstractBACKGROUND: Testicular sperm retrieval can lead to paternity for azoospermic patients with spermatogenic failure. The human BOULE gene, a meiotic regulator of germ cells, is a gene whose altered expression may be associated with sterility. We determined the levels of BOULE transcripts in the testes of azoospermic patients, and evaluated the relationship between BOULE transcript levels and patients' testicular phenotypes, clinical parameters and sperm retrieval results. METHODS AND RESULTS: BOULE transcript levels in the testes of 41 azoospermic patients were examined by quantitative competitive-reverse transcription-polymerase chain reaction. A significant decrease in BOULE transcript levels was detected in patients with spermatogenic failure, and BOULE transcript levels progressively decreased with increasing severity of testicular failure. BOULE transcript levels did not correlate with the serum hormone parameters measured. Significantly higher BOULE transcript levels were detected in 19 patients with successful sperm retrieval than in 12 patients with failed sperm retrieval. When using a cut-off value of 0.5 for BOULE transcript ratio to predict the success of sperm retrieval, both the sensitivity and specificity value were 100%. CONCLUSIONS: We suggest the BOULE transcript plays an important role in human spermatogenesis and that the levels may predict the presence of testicular sperm in patients with spermatogenic failure.
Identification of Two Novel Mutations in KDM3A Regulatory Gene in Iranian Infertile Males
AbstractBackground: KDM3A is a key epigenetic regulator expressed in the testis and is required for packaging and condensation of sperm chromatin. To this point, the association of the KDM3A gene with infertility has not been studied in human. The aim of this study was to screen any new mutation in KDM3A gene to explore more details of human male infertility. Methods: In this work, 150 infertile men (oligozoospermia and azoospermia) and 150 normal healthy fathers were studied. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing were used to screen any mutation in exons 12, 22, and 24 of KDM3A. Results: The infertile men showed various SSCP patterns for the exons 12 and 24, but not for exon 22. A transversion point mutation in exon 12 and a single nucleotide deletion in exon 24 were detected using sequencing analysis. The transversion mutation was located in the preceding exon of lysine-specific demethylase1 and Jumonji (Jmj)-C domain and the later one (deletion) in the cupin-like motif of KDM3A protein. Neither Y chromosome microdeletions nor partial azoospermia factor deletion was found in these patients. Conclusion: The mutations found in infertile men with otherwise unexplained severe spermatogenic failure could be considered as the origin of their abnormalities.
GPR56 gene down-regulation in patients with Klinefelter syndrome: a candidate for infertility?
AbstractBACKGROUND: The etiology of azoospermia in patients with Klinefelter Syndrome (KS) is still unknown. The protein codified by the G protein-couple receptor 56 (GPR56) belongs to the adhesion family of G protein-coupled receptors (GPRs). Its mutations are involved in the pathogenesis of intellectual disability and, according to animal studies, infertility. As the expression of GPR56 in patients with KS has not been investigated so far, this study was undertaken with the purpose of evaluating its expression in peripheral blood mononuclear cells (PBMCs) of patients with KS and normal controls. METHODS: This age-matched case-control study was performed in 10 patients with KS and 10 controls. Patients and controls underwent to blood sampling for next-generation sequencing (NGS) analysis, and differentially expressed mRNAs were identified using DESeq2 v.1.12. QRT-PCR was used to validate the results obtained by NGS analysis. TaqMan Gene Expression Assay primers were used to carry out the real-time PCR analysis for GPR56. RESULTS: GPR56 was down-regulated by -2081-fold (q-value <0.05) in PBMCs of patients with KS compared to controls. NGS data were confirmed by QRT-PCR. CONCLUSIONS: The possible contribution of the GPR56 gene down-regulation in the pathogenesis of spermatogenic failure in patients with KS is worthy to be further explored.
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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