Developing a Duchenne Muscular Dystrophy Therapeutic Agent with a New Base Editing Technology
Abstract
Objective: We intend to utilize a proprietary novel gene editing technology, called Pin-point base editing platform, to develop once-and-done therapeutics that can provide permanent improvement to Duchene Muscular Dystrophy (DMD). Rationale: DMD is one of the most severe muscle diseases, affecting ~1 in 5,000 boys and causing premature death. Most DMD cases are caused by genetic mutations in a large muscle gene called dystrophin. More than 3,000 different mutations on the dystrophin gene have been identified to cause DMD. Currently there is no cure for DMD; moreover, it is impractical to develop different therapeutics for treating patients with each mutation. Fortunately, the over 3,000 different mutations are clustered within so-called hotspot regions of the gene. This distribution pattern makes a therapeutic strategy called exon-skipping very powerful. In essence, exon-skipping removes a small fragment of the protein (termed exon) where mutations cluster, a strategy analogous to the amputation that is to remove an infected limp to save a person. The U.S. Food and Drug Administration (FDA) has approved three exon-skipping drugs, eteplirsen, golodirsen, and viltolarsen. However, these drugs do not function at the gene level and they do not lead to a permanent improvement. Mitigation of the disease requires lifelong costly injection of these drugs once every two weeks. CRISPR is a Nobel Prize Winning (2020) technology that works like scissors operating on DNA. It can potentially cut a disease-causing gene fragment out, a perfect tool for exon-skipping (gene amputation) at the DNA level. Indeed, the feasibility of CRISPR technology for DMD exon-skipping has been confirmed in animal models. However, the conventional CRISPR technology (“scissors-like”) is too harsh, which can potentially cause oncogenic DNA damage. Therefore, the risk is high when applying the conventional CRISPR technology for DMD treatment (e.g., may lead to cancer development). As such, major regulatory hurdles are expected from the FDA for approval of such therapeutics. The Pin-point base editing technology we developed is considered one of the latest generation of CRISPR technologies. It provides a much milder way to do a “surgical operation” on DNA by avoiding the oncogenic DNA cut. The technology has been independently validated by and licensed to Horizon Discovery Corporation, a UK public company and a global leader in gene editing. In this proposal, we describe the research to develop Pinpoint based therapeutics for DMD, including: (1) to design and screen for the best lead drug, (2) to package the drugs in an FDA-approved deliverable vector and test the efficacy and safety profile in cells, and (3) to test the efficacy and safety profile in a mouse DMD model. We expect that the drug leads will have a similar effect as the conventional CRISPR technology in providing permanent improvement for DMD, but is safer through minimizing the oncogenic liability. Ultimate applicability: 1. What types of patients will it help, and how will it help them? The prototype therapeutics is for exon 51 skipping, which would impact ~15% of DMD patients. The proof-of-principle in the mouse model will make the therapeutic strategy applicable to ~80% of DMD patients. The therapy would provide a once-and-done drug providing permanent or curative improvement to DMD patients. 2. What are the potential clinical applications, benefits, and risks? The potential clinical application will provide a restoration of the dystrophin function through modifying the gene; thus, one treatment would lead to a lifetime benefit. 3. What is the projected time anticipated to achieve a clinically relevant outcome? The proposed studies (2 years), if successful, may prepare the therapeutic lead for Investigative New Drug (IND)-enabling studies (1 year). After completing the IND-enabling studies, clinical trials may follow. An estimated 3-4 years is expected before clinica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110816
Entities
People
- Shengkan Jin
Organizations
- Rutgers University
- United States Army