Research Terms
Industries
| Ends | Title |
| 07-2025 |
Understanding and Improving Therapies for the Muscular Dystrophies
Understanding and Improving Therapies for the Muscular Dystrophies
NATL INST OF HLTH NIAM
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| 07-2023 |
Validation? of? NOX4? as? a? potential? target? to? re-balance? repair/replacement? in? BMD? and?identification? of? responsive? therapeutic? biomarkers
Validation? of? NOX4? as? a? potential? target? to? re-balance? repair/replacement? in? BMD? and?identification? of? responsive? therapeutic? biomarkers
FULCRUM THERAPEUTICS INC
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| 07-2021 |
Understanding and Improving AAV Gene Therapy for DMD
Understanding and Improving AAV Gene Therapy for DMD
PARENT PROJECT MUSCULAR DYSTROPH
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| 07-2021 |
Targeting senescent stroma in DMD
Targeting senescent stroma in DMD
MUSCULAR DYSTROPHY ASS
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This gene therapy combines the increased expression of GDF15 with a myostatin inhibitor to treat obesity or reduce weight while maintaining muscle mass. Obesity is a major health problem in humans and companion animals. It increases the likelihood of developing diseases such as diabetes, hypertension, coronary heart disease, stroke, and breathing problems, and it correlates directly with mortality risk. Although some available therapies, such as drug therapy and bariatric surgery, do treat obesity, they often cause side effects and other complications, threatening their effectiveness. Previous research has shown the loss of expression of growth differentiation factor 15 (GDF15) correlates with weight gain and worsened metabolic function in mice, making it a potential pathway for treating obesity. However, treatment with GDF15 leads to loss of muscle mass, abating its therapeutic effectiveness.
Researchers at the University of Florida have developed a gene therapy to treat obesity in humans and companion animals with no adverse side effects. By combining the administration of GDF15 and an inhibitor of myostatin, a known negative regulator of muscle growth, this therapy treats obesity while preventing the loss of muscle mass.
Gene therapy combining GDF15 and a myostatin inhibitor to treat obesity in humans and companion animals while preserving muscle mass
This gene therapy encodes for the expression of GDF15 combined with a myostatin inhibitor to treat obesity while preserving muscle mass. Loss of GDF15 correlates with weight gain and decreased metabolic function in mice, and previous research has demonstrated that treating mice with GDF15 improves metabolic health in animal models, making it a great potential target for treating obesity. However, although GDF15 decreases adipose tissue volume in mice, it also leads to a dramatic loss in muscle mass through stimulation of myostatin secretion from skeletal muscle, making it a poor therapeutic option on its own. To offset the atrophic effect of GDF15, this therapy combines the administration of GDF15 and an inhibitor of myostatin signaling. To obtain secretion of both GDF15 and the myostatin inhibitor, the inventors have created a bi-cistronic RNA using an internal ribosomal entry site (IRES), with a myostatin propeptide translation following GDF15. Thus, the combination treatment, creating secretion of both GDF15 and a myostatin inhibitor can be used to treat obesity in companion animals and, potentially, in humans. Design alternatives involve administration of GDF15 and the myostatin inhibitor as individual nucleotides, or as polypeptides. Different vectors can serve as delivery vehicles, including adeno-associated viral (AAV) vectors.
These recombinant adeno-associated virus (rAAV) capsids enable improved targeting of gene therapy to striated muscle while minimizing delivery to the liver. Duchenne Muscle Disorder (DMD) is a rare genetic disorder involving progressive muscle weakness and degradation due to the defective expression of the dystrophin protein. DMD patients experience initial dystrophy of external muscles, with an eventual impairment of heart and pulmonary function, resulting in a 100 percent fatality rate and a median life expectancy of approximately 28 years. rAAVs have emerged as vectors for the delivery of gene therapy in a number of different diseases, including DMD. However, the majority of delivery strategies involve systemic administration, reducing drug specificity and necessitating high doses, triggering several undesirable immune responses and serious adverse effects.
Researchers at the University of Florida have redesigned rAAV capsid proteins for the targeted delivery of gene therapy to striated muscles while minimizing delivery to the liver. By providing increased tissue-specificity, it enables a reduction in necessary doses, achieving higher efficacy, and reducing costs and safety concerns.
Targeted delivery of gene therapy to striated muscle while minimizing delivery to the liver and adverse immune responses
The use of recombinant adeno-associated virus (rAAV) has emerged as a therapeutic strategy for the delivery of gene therapy, but most therapies involve systemic administration, leading to adverse immune responses. These modified rAAV present one or more amino acid substitutions in the capsid proteins, leading to surface loops alterations that result in the targeting of receptors important for cardiac and skeletal muscle viral uptake. Consequently, these particles provide improved specificity to striated muscle and higher transduction efficiencies, achieving higher efficacy, minimizing undesired delivery to the liver and reducing costs and safety risks.
