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Targeting SARM1 as a Therapeutic Strategy for Autosomal Dominant Optic Atrophy (ADOA) and Leber Hereditary Optic Neuropathy (LHON)

Award Number: K99EY037821
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Targeting SARM1 as a Therapeutic Strategy for Autosomal Dominant Optic Atrophy (ADOA) and Leber Hereditary Optic Neuropathy (LHON) - Project Summary Mitochondria play a crucial role in maintaining neuronal health and function. Dysfunction of these organelles leads to various neurological diseases. Retinal ganglion cells (RGCs), the primary output neurons in the retina, are particularly vulnerable to mitochondrial damage. The two most common hereditary optic neuropathies characterized by RGC degeneration, Autosomal Dominant Optic Atrophy (ADOA) and Leber Hereditary Optic Neuropathy (LHON), both stem from mitochondrial dysfunctions. ADOA arises from mutations in OPA1, which regulates inner mitochondrial membrane fusion, while LHON is caused by mutations in the complex I subunit genes encoded by the mitochondrial genome. Currently, no effective treatments exist for either condition, underscoring a critical unmet need to unravel the disease mechanisms and develop therapies to safeguard RGCs from degeneration. The project’s significance lies in investigating the role of SARM1, a trigger of neurodegeneration, in mitochondria-induced RGC degeneration. Our lab has built a novel ADOA mouse model carrying the pathogenic Opa1R290Q/+ mutation. This model recapitulates key features of human ADOA, including mitochondrial fragmentation, aberrant glutathione redox, age-related RGC degeneration, and declines in RGC function. We found that knocking out Sarm1 in these ADOA mice nearly completely protects against all the degenerative phenotypes, suggesting that SARM1 activation drives RGC death in ADOA. Given the similarities between ADOA and LHON, we hypothesize that the same mitochondria-SARM1 pathway also contributes to LHON pathology. Therefore, the central hypothesis of the project posits that mitochondria-induced SARM1 activation leads to RGC death in both ADOA and LHON, and inhibiting SARM1 represents a promising therapeutic approach. Aim 1 of the proposal aims to identify specific mitochondrial defects triggering SARM1 activation in OPA1 mutant RGCs, and elucidate the underlying mechanisms. Aim 2 seeks to establish a dominant-negative SARM1-based therapeutic approach in ADOA mice. During the R00 phase in Aim 3, I will characterize a LHON mouse model and examine whether Sarm1 KO provides protective effects. I have assembled an advisory committee to provide conceptual and technical guidance as I pursue this study. Furthermore, I have also formulated a comprehensive training and career development plan to be executed during the grant period. This integrated proposal, encompassing the research plan and mentoring activities, will provide me with a solid foundation to embark on an independent academic career.


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 = $132,837 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Vision Research	000	1	4/17/2026	NEW	$132,837
														Subtotal = $132,837

Grand Total All Awards = $132,837

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Targeting SARM1 as a Therapeutic Strategy for Autosomal Dominant Optic Atrophy (ADOA) and Leber Hereditary Optic Neuropathy (LHON)

Award Number: K99EY037821

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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