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Targeting repeat expansion instability with de novo DNA slip-out binding proteins

Award Number: R21EB039470
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/22/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Targeting repeat expansion instability with de novo DNA slip-out binding proteins - PROJECT SUMMARY/ABSTRACT DNA repeat expansions, characterized by the abnormal expansion of genetically unstable, short, repetitive DNA sequences, cause over 60 REDs including Huntington's disease (HD), myotonic dystrophy, and spinocerebral ataxia, that result in a range of neurological and other health problems. While RED pathogenesis can arise from a variety of downstream mechanisms, including production of aberrant RNA accumulation and mutant protein aggregation, evidence is accumulating that a shared characteristic for multiple REDs is the somatic instability (SI) of DNA repeats that underlies disease progression. Emerging evidence for HD, the archetypal RED, suggests that disease onset occurs upon crossing a toxic threshold of repeat length as patients age, a likely feature of RED pathogenesis more broadly. Hence, we expect that a general therapeutic approach for REDs that rely on SI should target the mechanisms underlying the genetic instability. However, there are few approaches under exploration that can halt SI and that don't also alter normal processes by knocking down repair enzymes. This proposal's objective is to pioneer a novel gene therapy approach for halting somatic instability by developing new molecular tools that target DNA structure. By developing such tools, the aims of this proposal will overcome a critical limitation of existing genome targeting technologies that only recognize linear DNA sequence. We will pursue two parallel approaches, using HD as a paradigm RED, that serve to de-risk our overarching goal. In Aim 1, we will leverage AI-based computational methods for design of DNA-binding proteins that selectively target DNA hairpin or bulge structures that form at slip-outs of pathogenic expanded repeats. We will fuse these proteins with strand-selective nickases to test our hypothesis that slip-out selective nicking can induce repeat contractions. In Aim 2, as a secondary approach, we will engineer slip-out selective cytosine base editors to slow SI by stabilizing the DNA duplex through repeat interruption. To do this, we will leverage the natural properties of cytidine deaminase enzymes that act on ssDNA substrates. Finally, in Aim 3, we will stablish impact of slip-out selective molecular tools to induce contractions or slow SI in vivo in an HD knock-in mouse model. The expected outcome of this study will be development of a new technologies for structure-specific DNA targeting and a proof-of-principle demonstration of their use to induce repeat contractions or slow SI in HD. The high-risk-high impact nature of this proposal is aligned with the mission of NIBIB, the Biomolecular Technologies program area, and the explicit goals of the Trailblazer R21 mechanism for Early-Stage Investigators because of its focus on developing an exploratory molecular technology relevant to a broad spectrum of diseases.


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 = $246,208 )
2026	2026	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	8/21/2026	NEW	$246,208
														Subtotal = $246,208

Grand Total All Awards = $246,208

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Targeting repeat expansion instability with de novo DNA slip-out binding proteins

Award Number: R21EB039470

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/22/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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