August 2, 2023
Welcome to our first Researcher Spotlight, where we highlight our research partners and dive into the work they are doing to advance treatments for rare and ultra-rare diseases.
First up is Noah Weisleder, PhD, from the Weisleder Lab at the Ohio State University College of Medicine! In this conversation, we dive into the groundbreaking research being conducted at the Weisleder Lab and their partnership with Cure Rare Disease.
What does the Weisleder Lab research?
The Weisleder Lab at the Ohio State University College of Medicine is dedicated to improving our understanding of skeletal muscle and cardiovascular physiology, including the mechanisms behind membrane repair and calcium signaling in multiple diseases. In particular, we are investigating the function of various proteins in the repair of muscle cell membranes in inherited myopathies, inflammatory myopathies, heart failure and Alzheimer’s disease.
What is MG53?
MG53, or TRIM72, is a key component of membrane repair in muscle and one of many TRIM family proteins that the Weisleder lab is investigating. This protein, which is primarily located in skeletal and cardiac muscle, works to counteract membrane damage. In patients with diseases that result in fragile cell membranes leading to muscle cell death, however, the normal levels of MG53 protein available are not sufficient to compensate for the extent of membrane damage.
How is the Weisleder Lab working with CRD?
In collaboration with Cure Rare Disease, the Weisleder Lab is developing MyoTRIM, a protein-supplementation based therapeutic that delivers an improved version of MG53. This technology can potentially be applied as a treatment option for Duchenne muscular dystrophy and LGMD2b, as the genes affected in those diseases are too large to fit within an AAV vector usually used in gene therapy.
MyoTRIM is also designed to be a non-viral therapy, meaning it could provide therapeutic options to patients who have received gene therapy or have pre-existing antibodies to AAV therapies. This therapy could also be used in patients at any age and in patients with any dystrophin mutation.
Early testing and research into this approach of delivering an improved version of the MG53 protein shows promise in protecting muscle fibers from damage and we are excited to continue advancing the research.
What are Duchenne muscular dystrophy and Limb girdle muscular dystrophy type 2b?
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder with a prevalence of 1 in 3,500 male births. It is caused by mutations on the dystrophin gene, which is located on the X chromosome. The dystrophin protein works to protect muscle fibers from breaking down. Symptoms often present within a few years of age and can include difficulty walking or climbing stairs, delayed speech, and leg pain. Cardiac and pulmonary function can also decrease as the disease progresses.
Limb girdle muscular dystrophy (LGMD) type 2b is caused by mutations on the DYSF gene, which codes for a protein called dysferlin. Dysferlin is located in the sarcolemma, a membrane surrounding muscle fibers, and helps repair the sarcolemma. The protein may play a role in the inflammatory process. LGMD2b has a prevalence of approximately 7.4/1,000,000 and has an autosomal recessive inheritance pattern. Symptom onset generally occurs between 20 and 30 years of age and can include weakness in the pelvis and shoulders. Pulmonary involvement is sometimes present, but is not as severe as in some other types of muscular dystrophy.
What do you like about working with CRD?
Cure Rare Disease plays a vital role in moving forward the innovative science necessary to develop new therapies for rare and ultra-rare diseases. The research supported by CRD fills an important unmet need for overlooked patient communities, so we have been excited to work with the investigators contributing to these drug development efforts. The community of researchers assembled and supported by CRD are key for rapidly advancing these efforts and we have been honored to be part of these efforts through the work in our laboratory group.
What is your hope for the future of this technology?
I expect that as more therapies for rare neuromuscular diseases become available, we will begin to treat patients and will be able to convert these debilitating, and sometimes lethal, diseases into ones that can be managed chronically to extend patients life and healthspan. Patients will be treated with several therapies that address various aspects of the disease. MyoTRIM could be very useful in this situation, since it is not dependent on the specific disease, mutation type or the age of patients. This should mean that many patients will benefit from MyoTRIM, which is the goal of anyone who is working in this field.
We appreciate Dr. Weisleder for sharing these updates about the research being done in the Weisleder lab. Through their dedicated efforts, they are making significant strides towards advancing therapies for those affected by rare diseases and we are thrilled to have them as partners in our mission.