Long Noncoding RNA-Targeted Therapy Alleviate Duchenne and Becker Muscular Dystrophy
Abstract
Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are a heterogeneous group of inherited diseases affecting skeletal, smooth, and cardiac muscle that lead to progressive weakness and degeneration of muscle fibers. Heart failure and respiratory failure are the main causes of death in these patients. Although generally milder compared to DMD, about 60% to 70% of BMD patients develop cardiomyopathy at 28 years old on average, and heart failure from ventricular dilation is the main cause of death in these patients. It has been estimated that about 1 in 18,450 male births exhibit BMD, which is about one third the cumulative birth incidence of Duchenne muscular dystrophy. A recent survey of BMD incidence suggested that 1.38 in 10,000 male individuals suffer from BMD. Furthermore, prevalence tended to be higher for Hispanic individuals than non-Hispanic, white, or black individuals. Currently, there is no cure for this disease; treatment options for BMD include physical therapy and corrective orthopedic surgery. Physical therapy may also help by slowing muscle degeneration and alleviating immunosuppression to reduce muscle cell apoptosis. Supportive treatment strategies, including seizure control, reducing incidence of infections, and assisted ventilation likewise help improve patient survival. Hence, it is necessary to demonstrate the underlying molecular mechanism of BMD and develop innovative therapeutic strategies to alleviate the symptoms and improve the outcomes of BMD patients. More than 30,000 long noncoding RNAs (lncRNAs) have been identified in the human genome, but the functional importance of lncRNAs in regulating homeostasis and inherited genetic diseases is largely unknown. A few noncoding RNAs, particularly microRNAs and microRNA precursors, have been suggested to be upregulated in muscular dystrophy (MD). We recently demonstrated that one lncRNA, H19, directly associates with dystrophin (DMD) protein at its C-terminal zinc-finger domain. Chromatin variants/in-frame deletions involved in BMD and certain non-silent mutations identified in DMD result in defects in the protein’s ability to interact with H19, leading to elevated Ub-DMD levels and dystrophin degradation. H19-dystrophin interactions inhibit TRIM63-dependent, K48-linked polyubiquitination of dystrophin at Lys3584 (referred to as Ub-DMD) and prevent the subsequent degradation of the protein. Dystrophin protein is also subjected to phosphorylation and protein degradation in a MRCK-alpha and alpha-synuclein-dependent manner. Therefore, supplement of H19 or inhibition of the polyubiquitination of dystrophin would be promising to improve the physical strength and outcome of BMD and DMD patients. We developed an innovative H19 RNA oligonucleotide, conjugated with the muscle-enriching peptide Agrin (referred to as AGR-H19) which, along with the small molecule inhibitors targeting the polyubiquitination pathway of dystrophin. Hence, our study translates current understanding of long noncoding RNA biology into meaningful targeted therapeutics for BMD patients and certain DMD patients. The goal of this proposal is to determine the efficacy of lncRNA and small molecule inhibitor-based targeted therapies for restoring dystrophin stability and alleviating BMD symptoms. The realization of this proposal’s aims would therefore significantly advance the field of BMD and DMD research. While the nature of this project will not directly lead to clinical trials in the next 3-5 years, it will serve as the foundation of a new frontier of therapies for BMD and DMD patients who currently lack effective treatment options. It is anticipated that the proposed studies will investigate potential targeted therapies for BMD/DMD patients, applying lncRNA mimics and small molecule inhibitors targeting ubiquitination and phosphorylation events of dystrophin. Furthermore, combining these potential therapeutic strategies with current treatment options, such as exon-sk
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110842
Entities
People
- Chunru Lin
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army