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WHICH-ART: A Sperm Functional Assay to Guide Personalized ART Decisions

Award Number: R61HD123533
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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WHICH-ART: A Sperm Functional Assay to Guide Personalized ART Decisions - PROJECT SUMMARY/ABSTRACT Infertility affects 10% to 15% of couples worldwide, and an estimated 56.1% of those in developed countries seek assisted reproductive technologies (ART) treatment. A major clinical challenge in ART is that many men have normal semen parameters yet fail to achieve fertilization. In fact, ~20% of infertile men are classified as normospermic. Clinicians have no functional sperm biomarker to guide treatment selection among intrauterine insemination (IUI), conventional in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI). As a result, many couples undergo multiple unsuccessful ART cycles, accumulating emotional distress and financial burden. To address this gap, we developed WHICH-A.R.T., a rapid, plate-reader-based assay that uses compatible fluorescent dyes to quantify three alkaline-induced changes that sperm must undergo to be able to fertilize an oocyte: hyperpolarization of the membrane potential, intracellular calcium (Ca²⁺) increase, and intracellular pH change. We and others have shown that sperm membrane potential strongly predicts IVF fertilization success (two-pronuclei egg formation), and our pilot data demonstrate that membrane potential and Ca²⁺ changes predict IVF success with an area under the curve of 0.83. These proof-of-concept data indicate that WHICH- A.R.T. has the potential to personalize ART treatment for couples. If the assay is validated, a man whose sperm tests WHICH-A.R.T.-positive could be directed to IUI or IVF, as ICSI is unlikely necessary. Conversely, a man whose sperm tests WHICH-A.R.T.-negative could be guided to ICSI, as IUI and IVF will likely fail. Thus, WHICH-A.R.T. would support individualized, evidence-based treatment selection to reduce the time to pregnancy To optimize WHICH-A.R.T. and begin to test its clinical utility, we propose the following two-phase project: In the R61 phase, Aim 1 will rigorously validate WHICH-A.R.T. as a quantitative predictor of sperm fertilization success in IVF by establishing assay rigor, biomarker validity, and predictive thresholds for IVF outcomes. Aim 2 will define the optimal WHICH-A.R.T. testing window for IVF/IUI to determine whether WHICH-A.R.T. biomarker measurements are stable over time. The R33 phase (Aims 3-4) will then extend these validated biomarkers into triaging IUI candidates and guiding personalized treatment pathways. Aim 3 will validate WHICH-A.R.T. biomarkers as predictors of IUI success, and Aim 4 will develop and validate a machine- learning model that accurately predicts IUI success. Successful completion of this project will deliver the first functional sperm assay capable of predicting fertilization potential. If successful in future clinical trials, WHICH-A.R.T. could enable personalized ART selection, reduce ineffective cycles, and improve reproductive outcomes for couples with unexplained infertility.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $427,288 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	1	9/4/2026	NEW	$427,288
														Subtotal = $427,288

Grand Total All Awards = $427,288

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WHICH-ART: A Sperm Functional Assay to Guide Personalized ART Decisions

Award Number: R61HD123533

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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