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Engineered tissue arrays to streamline deimmunized DMD gene therapy vectors

Award Number: R33NS133080
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: 09/10/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Engineered tissue arrays to streamline deimmunized DMD gene therapy vectors - A major driver for immunogenicity is the presence of T-cell epitopes within a protein sequence that can activate helper T cells, resulting in neutralization of the therapeutic effect. For DMD gene therapy, the possibility of T-cell responses to pre-existing (from revertant fibers) &/or post-treatment dystrophin epitopes has recently emerged as a serious treatment issue. In the past year 5 DMD patients treated with AAV-microdystrophin ( Dys) have developed T cell mediated immune responses against dystrophin. Based on immunological data, in all cases the antigenic region was highly suggested to be encoded by exons 8-11. 1 Additionally, to being observed in patients deleted for this region (updates provided at MDA and ASGCT 2022 scientific conferences). A key component of our approach takes advantage of the fact that a single amino acid can anchor a novel peptide for a preferred binding state for antigen presenting cells’ via its major histocompatibility complex (MHC) and subsequent T cell receptor (TCR). It is the TCR recognition which leads to downstream signaling cascades and immune sequelae. Alternatively, conservatively modified residue(s), can disfavor antigen presentation, preventing dystrophin specific immunity. Thus, avoidance of a specific immune response can be achieved if key epitope anchor residue(s) necessary for antigen presentation are modified to disrupt MHC recognition. Here, our proposal addresses the fundamental role of immunogenicity against dystrophin that has been found in DMD patients. This proposal integrates deimmunization protocols and structure-based protein redesign via Rosetta-software, with streamlined functional testing via our magnetic tissue array (Mantarray) platform-allowing for daily 3D DMD contractile performance assessment in-a-dish. In turn, dystrophin epitopes can be predicted & ranked according to their antigenicity by correlating their amino acid sequence content with immunological databases. Known and predicted epitopes will be targeted for redesign to reduce or eliminate putative MHC-binding peptides and subsequent T cell activation. Our deimmunization approach will build on previous efforts while focusing on exons 8-11 of dystrophin, & integrating data as it becomes available through any DMD clinical trial alliance that unfolds. The exon 8-11 region, now part of Pfizers’ updated patient exclusion criteria, encodes a portion of the actin binding domain, extending through spectrin-like repeat 1 (note: we have already deimmunized much of exons 6 8). Importantly, restricting deimmunization efforts to exons 8-11 of dystrophin would be beneficial for all Dys designs currently in clinical trials. In summary, we propose to deliver deimmunized Dys vectors to human DMD 3D engineered muscle tissues and measure contractile force(s) via our Mantarray system in an effort to screen for highly functional leading candidates with reduced immunogenicity. To fully validate our 3D muscle system as a predictive model we will test optimized candidates(s) via rAAV vectors driven by highly muscle specific regulatory cassettes for their capacity to ameliorate disease progression in the DMD mdx rat model of DMD. These results will provide necessary preclinical outcome metrics required to advance towards Phase 1 clinical trials.


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 = $450,758 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/10/2026	EXTENSION WITH OR WITHOUT FUNDS	$450,758
														Subtotal = $450,758

Grand Total All Awards = $450,758

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Engineered tissue arrays to streamline deimmunized DMD gene therapy vectors

Award Number: R33NS133080

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: 09/10/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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