Wednesday, December 31, 2025 12/31/2025

Microgial contribution and therapeutic potential in Friedreich's ataxia

Award Number: R01NS135162
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Microgial contribution and therapeutic potential in Friedreich's ataxia - Project Summary Friedreich’s ataxia (FRDA) is a multi-systemic autosomal recessive disorder that is predominantly caused by a homozygous GAA repeat expansion mutation within the first intron of the frataxin (FXN) gene leading to a decrease of protein expression. Frataxin is a mitochondrial protein involved in iron metabolism. FRDA is characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy. There is no treatment for this lethal disease. We tested a new therapy for this disease consisting of wildtype (WT) hematopoietic stem and progenitor cell (HSPC) transplantation in the Y8GR mouse model of FRDA. This therapy worked beyond our expectation in FRDA completely correcting the neurologic, muscular and cardiac complications after a single infusion of HSPCs in lethally irradiated Y8GR mice. We optimized an autologous CRISPR/Cas9-mediated gene correction HSPC approach for FRDA and we are now conducting the investigational New Drug-enabling studies for the clinical translation of this approach. Addressing the mechanism of action, we previously showed that tissue rescue was at least partly mediated by transfer of frataxin from HSPC-derived microglia-like cells to diseased neurons. The exact mechanism of rescue including how microglial replacement and frataxin transfer from microglia-like cells to neurons contributes to this rescue are still unknown. Very few studies investigated the role of microglia in the pathogenesis of FRDA. We believe that the impressive response of the FXN- expressing HSPC transplant is due to, not only the transfer of FXN into neurons, but also to the rescue of the microglial phenotype. The central hypothesis is that these findings in the mouse model are translatable such that CRISPR-editing of the GAA repeat expansion in HSPCs in FRDA will lead to both functional rescue of microglia-like cells and transfer of FTX to neurons. Applying a novel cohort of induced pluripotent stem cells from FRDA patients, controls, and importantly lines created with the proposed gene editing, we find a dramatic phenotype in FRDA microglia that is corrected by editing. We will utilize novel in vitro and in vivo methods including patient-derived organoids (mini-brains) and a murine xenotransplantation model of human microglia to ascertain the microglial contribution to FRDA pathogenesis, the potential for gene editing to correct this phenotype, and the mechanisms and functional ramifications of FTX transfer to neurons from microglia. . This project is significant because it provides a human specific platform for disease modeling and validating novel therapeutic approaches and provides supporting evidence that CRISPR HPSC transplantation can be used to treat FRDA. It will also advance the understanding of microglia-neuron interactions, and open new perspectives for the treatment of neurodegenerative diseases due to mitochondrial dysfunction.


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 = $523,295 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/12/2025	NON-COMPETING CONTINUATION	$523,295
														Subtotal = $523,295

Issue Date FY: 2025 ( Subtotal = $585,180 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/3/2024	NON-COMPETING CONTINUATION	$526,660
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/8/2025	NON-COMPETING CONTINUATION	$58,520
														Subtotal = $585,180

Issue Date FY: 2024 ( Subtotal = $590,166 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/14/2023	NEW	$590,166
														Subtotal = $590,166

Grand Total All Awards = $1,698,641

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Microgial contribution and therapeutic potential in Friedreich's ataxia

Award Number: R01NS135162

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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