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CRISPR/Cas9-Mediated Therapeutic Targeting of CAG Repeats in Spinocerebellar Ataxia Type 12

Award Number: R61NS149087
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: 09/21/2026
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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CRISPR/Cas9-Mediated Therapeutic Targeting of CAG Repeats in Spinocerebellar Ataxia Type 12 - PROJECT SUMMARY Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant neurodegenerative disease caused by a CAG/CTG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of phosphatase 2A (PP2A). SCA12 is notable clinically for tremor, gait abnormalities, and neuropsychiatric syndromes, and neuropathologically for atrophy in cerebral cortex and cerebellum. By CRISPR/Cas9 assisted homologous recombination, we have generated a novel SCA12 knock-in mouse model and four sets of human isogenic control and SCA12 iPSC lines, which are useful tools for the investigation of SCA12 pathogenesis. Compared with controls, SCA12 knock-in mouse cortical brains showed differential gene expression changes at the age of 6 months. In addition, SCA12 knock-in mice developed motor deficit phenotypes, compared with control littermates at the age of 15 months. It is worth noting that since the CAG repeat expansion is located in the 5’ UTR or noncoding regulatory region of most PPP2R2B transcripts, its excision would not affect the open reading frames (ORFs) of the major protein isoforms Bβ1 and Bβ2 expressed from the PPP2R2B gene locus , therefore the CAG repeat removal potentially represents an appealing therapy for SCA12. We have identified gRNAs in the CAG repeat flanking regions to remove the repeat expansion in SCA12 using the CRISPR/Cas9 approach. Our preliminary data indicates that overexpression of spCas9 and paired gRNAs had ~70% efficiency in repeat removal in a homozygous SCA12 hiPSC line. In addition, we have established stable, genetically engineered hiPSCs for producing extracellular vesicles (EVs) with RVG expression, offering the improved ability for brain-targeted drug delivery. We therefore propose to explore the use of intravenously delivered RVG-modified hiPSC-derived EVs for CRISPR/Cas9-mediated CAG repeat removal in human SCA12 iPSC-derived cortical neurons as well as the SCA12 knock-in mouse model, as a potential therapeutic approach for this disease.


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 = $581,250 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/19/2026	NEW	$581,250
														Subtotal = $581,250

Grand Total All Awards = $581,250

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CRISPR/Cas9-Mediated Therapeutic Targeting of CAG Repeats in Spinocerebellar Ataxia Type 12

Award Number: R61NS149087

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: 09/21/2026

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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