Expression of enhanced dystrophins via AAV
Gene therapy for DMD is aimed at treating the cause of the disorder: a lack of dystrophin. Currently, the only known method for dystrophin delivery to muscles bodywide is by infusion of adeno-associated viral (AAV) vectors carrying miniaturized dystrophin genes. These AAV-microdystrophin (µDys) vectors have shown dramatic effects in animal models and are being tested in clinical trials. However, the observation of serious adverse events (SAEs) in 5 patients who were missing (deleted for) a part of the gene that is carried by µDys vectors has shown that parts of dystrophin can lead to a serious immune response in some patients. The immediate consequence of this has been that such patients (10-15% of all DMD boys) are being excluded from gene therapy trials. Our group has been studying dystrophin immunity for many years due to concerns that such a situation might emerge, and we have developed a computational method to predict immunogenic regions of dystrophin and to redesign vectors to remove problematic parts of the protein. To date we have successfully redesigned several portions of micro/mini-dystrophin and shown that they can be functional, stable and non-immunogenic in animal models. Here we propose to extend these studies to the problematic region recently identified in the clinic. Our goal is to develop modified dystrophin clones that could be used in clinical trials and thus allow broad enrollment of patients regardless of their underlying genetic mutation.
https://doi.org/10.55762/pc.gr.159120
Grantee: Jeffrey Chamberlain, PhD
Grant type: MDA Request for Applications
Award total: $200,000
Institution: University of Washington
Country: Washington, United States
Maximizing dystrophin functionality
Gene therapy for Duchenne muscular dystrophy is an extremely promising approach to therapy as it directly addresses the cause of the disorder- a lack of functional dystrophin protein. Our group has spent more than 30 year studying the structure and function of dystrophin and developing approaches for gene therapy. This work includes development of numerous micro-dystrophin clones, several of which are being tested in clinical trials. We also showed that AAV vectors could be used for systemic delivery of new genes to muscles, bodywide. However, while current AAV-microdystrophin vectors are showing significant benefit in the clinic, several limitations have been identified. Among these are a lack of full function from micro-dystrophins, lower levels of dystrophin production than are ideal, and some vector dose limitations due to adverse events. Our proposal explores a new way to make larger mini-dystrophins and even full-sized dystrophin by co-delivery of current and novel AAV vectors. Here we explore the potential of this system to improve upon approach for gene therapy of DMD and other neuromuscular disorders.
https://doi.org/10.55762/pc.gr.158724
Grantee: Jeffrey Chamberlain, PhD
Grant type: Restricted Research Grant
Award total: $233,243
Institution: University of Washington
Country: Washington, United States
Summer 2020 - Jeffrey Chamberlain, PhD
"Our new approach will continue development of a novel approach to delivering larger, possibly up to full-length, dystrophins."
Jeffrey Chamberlain, Ph.D., Professor and McCaw Endowed Chair of Muscular Dystrophy at the University of Washington School of Medicine, was awarded an MDA restricted research grant totaling $471,693 over two years to develop improved dystrophin vectors that can deliver larger and more functional dystrophins to muscles throughout the body in patients with Duchenne muscular dystrophy (DMD).
Current approaches for DMD gene therapy rely on AAV delivery of micro-dystrophin or gene editing tools, which each produce smaller than normal dystrophins. Dr. Chamberlain plans to develop improved dystrophin vectors than can produce larger and more functional dystrophin to muscles of DMD patients. If successful, this technology would be applicable to any DMD or Becker’s muscular dystrophy (BMD) patient.
Grantee: Generation of large dystrophins in muscle via AAV vector delivery - Jeffrey Chamberlain, PhD
Grant type: Restricted Research Grant
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Grant - Summer 2016 - FSHD - Joel Chamberlain, Ph.D.
Joel Chamberlain, research associate professor at the University of Washington School of Medicine in Seattle, was awarded an MDA research grant totaling $300,000 over a period of three years to increase understanding of the role of DUX4 protein in facioscapulohumeral muscular dystrophy (FSHD).
In the muscle cells of people with FSHD, too much of a protein called DUX4 is made, leading to cell death. To determine how excess DUX4 results in muscle damage in FSHD, Chamberlain and colleagues will examine DUX4 protein production in a range of human biopsy samples in an effort to determine the cellular location of DUX4 and the protein’s relationship to disease-related changes in the muscle.
In parallel, in studies conducted in a unique mouse model of FSHD developed in Chamberlain’s lab, the team also will examine the toxic effects of expressing very low levels of the DUX4 protein. These studies will help assess how DUX4 initiates a chain of events that cause the slow, progressive muscle damage seen in FSHD.
Chamberlain’s work may reveal drug targets and inform the development and testing of therapies for FSHD.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: FSHD – Joel Chamberlain, Ph.D.
Grant type: Research Grant
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Grant - Summer 2012 - FSHD — Joel Chamberlain, Ph.D.
Joel Chamberlain, research assistant professor in the department of medicine at the University of Washington in Seattle, was awarded an MDA research grant totaling $330,780 over three years to study a therapeutic approach called RNA interference (RNAi) for the treatment of facioscapulohumeral muscular dystrophy (FSHD).
"Despite the surprising complexity of the FSHD disease pathway, several lines of research converge to identify DUX4 protein production as the final step in the disease pathway," Chamberlain says.
Now, Chamberlain and colleagues are working to develop a therapy that targets production of DUX4 through interaction with DUX4 messenger RNA, or mRNA. (RNA is a chemical cousin to DNA and is involved in a chain of steps between DNA and cellular protein production.)
"To carry out RNAi, we will use an RNA that specifically binds to the DUX4 mRNA and directs the cell to destroy the target DUX4 mRNA," Chamberlain explains. "Once inside the muscle, the RNA made to carry out RNAi is produced continuously to treat disease and is expected to remain active for many years."
The team also is working to create a mouse model of FSHD that mimics the human disease. The investigators will use the model — as well as new cell and mouse models from collaborating laboratories — to test their DUX4 RNAi approach. They plan to make the model available to other researchers for the testing of additional potential therapies.
"We have developed this targeted approach, referred to as RNA interferenceor RNAi, to reverse disease," Chamberlain says. "It works well in mouse models of muscular dystrophies, and we are the only laboratory to have succeeded in changing the course of the disease by delivering this therapy to all the muscles of the mouse with a single intravascular (into a blood vessel) injection."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: FSHD — Joel Chamberlain, Ph.D.
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Grant - Additional Grants 2013 - DMD/BMD — Jeffrey Chamberlain, Ph.D.
Jeffrey Chamberlain, a molecular biologist at the University of Washington, Seattle, was awarded an MDA grant of $328,628 over one year (through Jan. 31, 2014) to develop gene therapy delivery vehicles ("vectors") for gene transfer in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Chamberlain will develop gene transfer vectors derived from adeno-associated viruses (AAVs). They'll be designed to carry miniaturized versions of the gene for the dystrophin protein, which is missing in DMD-affected muscles and deficient in muscles affected by BMD. The studies are directly related to moving gene therapy for DMD/BMD into clinical trials.
Grantee: DMD/BMD — Jeffrey Chamberlain, Ph.D.
Grant type: Research Grant
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