Use of Macrophages for Targeted Dual Antisense Delivery to Treat DMD
Abstract
Challenges Addressed: This proposal will address following FY20 DMDRP focus areas: 1. Drug delivery to skeletal muscle and heart by overcoming biological barriers to delivery. 2. Addressing secondary pathologies to augment therapies directed at primary disease mechanism in young and aging DMD patients. Background: Recent years have seen a renaissance in genetic therapies for rare and debilitating chronic diseases. This is enabled in part due to increased safety and precision in their delivery. One such genetic therapy that has been demonstrated to be safe and effective for clinical use for multiple neuromuscular diseases is antisense oligonucleotides (AOs)-based therapies. Duchenne Muscular Dystrophy (DMD) is one such disease where AOs have been approved by the FDA as a viable genetic therapy for the affected boys. This class of drug allows production of internally truncated dystrophin protein that performs the essential functions performed by the full-length dystrophin protein. These therapies are thus continuing to gain prominence, with two new phosphorodiamidate morpholino oligonucleotide (PMO) drugs - Vitolarsen and Golodirsen receiving FDA approval just this year. Existing Bottleneck Being Addressed: While safety is a big draw for the use of this therapy, a problem plaguing all the current PMO-based AO drugs is their poor delivery to myofibers after being systemically administered. This leads to (1) poor dystrophin restoration and (2) need for large dose of drug to see any efficacy, which leads to these therapies being cost-prohibitive. Thus, there is a pressing need to develop approaches that address these challenges in order to enable these therapies to become more efficacious and affordable for ALL patients. One of the challenges in developing such approaches is lack of animal models that faithfully mimic some of the key deficits observed in patients that are the reason for the bottleneck in efficient AO delivery in human clinical trials. Innovation: A clue towards addressing the challenges due to poor AO delivery for dystrophin restoration came from our published studies that identified that macrophages and myoblasts work together to facilitate delivery of the systemically administered AOs to the muscle fiber. Infiltrating macrophages near the injured myofibers were shown to sequester circulating AOs, serving as local reservoir for AOs to the fusing myoblasts to deliver it to the regenerating myofibers. The second innovation that has enabled the proposed study is our recent study identifying D2-mdx as a mouse model that demonstrates high levels of TGFß and low levels of myogenic regeneration, the two bottlenecks in use of AOs for treating patients. These innovative findings and tools enable this proposal that aims to use them for the purpose of developing an innovative approach that would allow addressing the issue of poor AO delivery, while simultaneously improving muscle health in DMD boys. Impact: The studies in this proposal builds upon the abovementioned recent findings by our group that pertain to two of the bottlenecks in development of effective therapies to address the overcome limitations in the current AO-based treatment of DMD. The proposed study will make use of AOs to simultaneously lower TGFß and increase dystrophin production, providing an all AO-based tool novel combinatorial therapy that will enhance the efficacy of current AO-based therapies for DMD while simultaneously enhancing muscle regeneration and reducing fibrotic muscle degeneration. If validated, our studies will lead to paradigm shift in development of approaches that augment the impact of the approved AO-based genetic therapies not only for DMD, but also for other muscular dystrophies associated with chronic muscle inflammation and reduced regeneration. Importantly, our proof-of-concept in vivo studies in this relevant animal model for DMD will also enhance testing other approaches for such synergistic enhancement of AO
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110680
Entities
People
- Jyoti K. Jaiswal
Organizations
- United States Army