Epigenetic diagnostic for severe spermatogenic failure and associated malignancy risks

The National Institute of Child Health and Human Development awarded $1,167,156 to Inherent Biosciences, Inc. on September 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to develop an epigenetic diagnostic for non-obstructive azoospermia and associated malignancy risks.

This Phase II SBIR project funds development of a novel diagnostic test that detects MSH5 epigenetic modifications linked to severe male infertility and elevated cancer risk. The test addresses a significant clinical gap: current diagnostic tools including karyotyping and Y-chromosome microdeletion testing fail to identify approximately one subset of non-obstructive azoospermia cases caused by DNA repair deficiencies. Prior research demonstrates that MSH5 epimutations occur in up to 19 percent of NOA patients and could be detected with high sensitivity and accuracy, establishing the feasibility of a non-invasive diagnostic that evaluates both fertility status and systemic health risks.

Inherent Biosciences will perform work at its facility in Salt Lake City, Utah, through August 31, 2028. The assistance type is a project grant. This award represents a direct-to-Phase-II SBIR funding decision, reflecting successful completion of Phase I work demonstrating technical feasibility and commercial potential.

Abstract

/summary direct to phase II sbir title: epigenetic diagnostic for severe spermatogenic failure and associated malignancy risks male infertility affects an estimated 7 million men in the U.S. And contributes to nearly 50% of infertility cases. Non-obstructive azoospermia (NOA), the most severe form of male infertility, affects approximately 1% of men globally (~40 million) and is particularly concerning due to its association with increased risks of cancer and cardiovascular disease. Current diagnostic tools for NOA, including karyotyping and y-chromosome microdeletion (YCM) testing, fail to address a significant subset of NOA cases, which are linked to DNA repair deficiencies. Prior research, including work from DR. Dolores lamb's laboratory shows that compromised DNA mismatch repair (MMR) and double-strand break (DSB) repair, along with genomic instability, are present in the majority of NOA patients. This suggests a functional link between the increased cancer risk in NOA men and the broader implications for their overall health. More recent work from DR. Lamb, in collaboration and support from inherent biosciences, identified epigenetic modifications in MSH5, a DNA repair protein, in up to 19% of NOA men, confirming a novel molecular pathway that could explain a significant subset of idiopathic NOA cases and provide a potential therapeutic target. This work provides strong evidence that MSH5 epimutations play a critical role in spermatogenic failure, while also linking these epigenetic alterations to systemic health risks such as cancer. Previous research demonstrated that MSH5 epimutations could be detected with high sensitivity and accuracy, providing a foundation for the development of an innovative diagnostic tool for NOA. This tool has the potential to address the unmet clinical need for a more comprehensive, non-invasive test that evaluates both fertility and systemic health risks (including multiple cancers) in men with NOA. The proposed 24-month direct to phase II study aims to commercialize this work while also defining the incidence of MSH5 epimutations in a broader cohort of NOA patients through multi-site clinical analysis. A semen-based reflexive diagnostic test will be developed to eliminate the need for additional blood samples, improving clinical utility and ease of use. Additionally, we will confirm the incidence of MSH5 epimutations in 500 colorectal cancer patients, a population known for DNA mismatch repair defects. The assay will be validated in a clia-certified laboratory for commercialization as a laboratory developed test (LDT). These efforts will integrate the MSH5 diagnostic into inherent biosciences' growing suite of NOA tools, which includes assays for predicting sperm presence and detecting klinefelter's syndrome and YCM, ultimately providing a comprehensive, streamlined diagnostic solution that enhances both fertility care and systemic health outcomes for men.