Targeted Cell-Based Gene Therapies for Persistent Exon Skipping and Dystrophin Restoration in DMD
Abstract
Muscular dystrophies are genetic disorders characterized by extensive muscle loss, inflammation, and fibrosis. One such disease, Duchenne muscular dystrophy (DMD), is characterized by chronic muscle damage, inflammation, and muscle loss due to the lack of the muscle structural protein dystrophin. Antisense oligonucleotide (AO) drugs are designed to exclude mutations present in the DMD patient s dystrophin gene to restore a shorter version of the dystrophin protein, effectively targeting the underlying genetic cause of the disease. This class of drug currently remains the only approved genetic therapy for DMD, with two new phosphorodiamidate morpholino oligomer-based AO drugs – Viltolarsen and Golodirsen – having just received Food and Drug Administration approval for DMD this past year. Despite their great potential for DMD and other neuromuscular diseases, AOs have failed to meet their clinical expectations due to their inefficient delivery to skeletal muscle. Our recent work aims to address this major challenge for AOs and has identified a prominent role for macrophages in the targeted delivery of AO to muscle stem cells and muscle fibers. Macrophages normally function within the diseased muscle to clear out the debris associated with chronic muscle damage, and also are required for muscle repair. Importantly, we found that macrophages accumulate the AO drug within the inflamed muscle they target, and subsequently provide it to actively repairing muscle fibers and muscle stem cells for dramatically longer than the drug circulates within the blood. This greatly extends the AO drug s bioavailability and resulting efficacy in the muscle tissue, and highlights therapeutic avenues to improve muscle drug delivery in the context of muscular dystrophies. Based on our recent work, we propose to develop a cell-based strategy for AO delivery using macrophages as drug delivery vehicles, to achieve efficient and long-term treatment of chronically-inflamed muscle tissue in DMD. To do so, we will harness the natural ability of macrophages to infiltrate dystrophic muscle to deliver virally expressed AOs to chronically-inflamed muscle tissue. Importantly, this approach will effectively eliminate excessive drug clearance by the kidneys and liver, enhance muscle tissue-specific delivery, and prolong the direct bioavailability of these AO drugs to muscle fibers, leading to improved drug efficacy and improvement of muscle function. Apart from enhancing muscle tissue-specific AO delivery and bioavailability, our strategy would prevent the need to frequently administer costly, high doses of AO drugs or the overwhelmingly high quantities of viral particles required in direct, viral gene therapy approaches currently under clinical development. Lastly, since DMD and most other muscular dystrophies entail severe tissue inflammation, the use of inflammatory cells, such as macrophages, as a tool for AO or gene therapy delivery may find broad use for other muscle diseases. The proposed investigations will build on our recent efforts and findings to explore the potential clinical application of inflammatory cell-based gene therapy delivery strategies for DMD. This work aims to overcome the major challenges to efficient muscle-specific drug delivery in order to improve the effectiveness of these drugs for DMD patients. This proposal aligns with the Fiscal Year 2020 Duchenne Muscular Dystrophy Research Program Focus Areas including – (1) cell-based therapies for improved drug delivery, (2) strategies for safe/efficient delivery to skeletal muscle and heart, (3) strategies to facilitate repeat viral gene therapy administration, (4) approaches to efficiently target muscle stem cells, and (5) approaches to improve drug delivery/efficacy for both young and aging DMD patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110711
Entities
People
- James S Novak
Organizations
- United States Army