The Role of Circular-Utrophin RNAs for Muscle Sparing in DMD
Abstract
Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy during childhood. DMD is caused by mutations of the DMD gene that encodes for the dystrophin protein and is critical for muscle membrane integrity. Thus, the absence of dystrophin due to mutations causes destabilized muscle membrane structure, leading to induced muscle damage after physical activity. While most limb muscles are severely affected in DMD, a few craniofacial muscles, such as extraocular muscles (EOM), are spared from damage. Although several hypotheses have been proposed to explain why certain muscles are spared from DMD pathology, none of them have been proven. Compensation by utrophin, an protein exhibiting similar structure with dystrophin, has been proposed; however, the contradictory EOM phenotypes of 2 dystrophin/utrophin double knock out (dKO) mice have led to controversial conclusions. We hypothesize that the sparing mechanism of EOM was disturbed by one dKO generating strategy but not the strategy used to create the other one. Although both dKOs were generated by interrupting middle of specific exons by a large gene insult, transcripts before target exons and its byproducts, such as circular RNA by back splicing, were still detectable. Since circular RNAs are known to express with tissue specific manner, we identified EOM specific circular-utrophin RNAs that could be disrupted by one of the dKO generating strategies. Here, we propose to determine the mechanism of the circular-utrophin RNA biogenesis and stability in EOM (Aim 1) and the role of circular-utrophin RNAs in the DMD-sparing mechanism (Aim 2). By completion of both aims, we anticipate that circular-utrophin RNA could be a target of potential gene therapy to protect individual muscles from DMD pathology. If the circular-utrophin RNA recovers fragile membranes of DMD muscles, this therapy will be able to target all stage of DMD. In this case, clinical application of circular-utrophin RNA-targeting therapy could be possible within 3 years due to rapid development of gene delivery technology using RNA-mediated stabilization. However, further research will be required to examine adverse effects or delivery efficiency in the affected muscle tissues. Taken together, this project will likely to develop a new gene therapy tool to treat DMD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211040
Entities
People
- Hyojung Choo
Organizations
- Emory University
- United States Army