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Gene Therapy Development for Muscular Dystrophy


Muscular dystrophy (MD) is identified as a genetic disorder and severe myopathy caused by mutations in the DMD gene encoding the dystrophin protein. Generally, the most direct approach to treating this disease can the expressions of the associated defective proteins. Recent progress has greatly increased the prospects for successful gene therapy of MD, and both viral and non-viral vectors have shown to deliver recombinant versions of defective genes. Several promising strategies in gene therapy for MD have been explored in clinical trials, including gene transfer, stop-codon read through approaches, and oligonucleotide mediated exon skipping and gene modification for cell therapy. Creative Biolabs has been occupied in the research of gene therapy for more than ten years and focuses on the field of inherited diseases research with a strong basic platform that can help you with gene therapy development for MD.

Model of dystrophin and the dystrophin-glycoprotein complex (DGC) in skeletal muscle Figure 1. Model of dystrophin and the dystrophin-glycoprotein complex (DGC) in skeletal muscle (Ramos 2015)

Structure and Function of Dystrophin in Muscle

Detailed knowledge of the structure and function of the dystrophin gene is conducive to design the gene therapy strategy for MD. Dystrophin gene is 2.2 Mb in size and expressed in muscle and non-muscle tissues with numerous isoforms. A major reason that the gene displays the highest known spontaneous mutation frequency of any human gene is likely caused by the enormous size of the locus. The dystrophin protein is necessary to nucleate the assembly of the dystrophin-glycoprotein complex (DGC) at costameres and the DGC with the function to links the internal cytoskeleton to the extracellular matrix. Currently, the basic gene therapy strategies for MD include the dystrophin gene delivery to replace the mutated gene and directly correct the defective genes by genome editing.

Featured Services for Muscular Dystrophy Gene Therapy

Despite tremendous obstacles for MD treatment based on gene replacement including enormous size of the gene and the large volume of muscle tissue, progress in the MD knowledge makes this approach possible. Previous studies have reported that the advent of mini-genes with a size of less than 7 kb allowed direct intramuscular gene transfer using viral vectors. Improved helper-dependent adenoviral vectors (HDAds) can deliver the cassettes expressing the full-length dystrophin protein via intramuscular injection. In addition, several studies have shown that recombinant vectors derived from adeno-associated virus (AAV) can lead to long-term expression and dystrophy can be almost entirely halted and largely reversed in an adult mammal via systemic deliver of AAV/micro-dystrophin vectors. The synthetic gene of smaller but highly functional mini-and micro-dystrophin cDNAs and the improved deliver system is of great benefit to the application of gene therapy for MD.

With the identification of most MD-causing mutations, reading frame in deletion-mutations can be recovered by removing additional exons in the proximity. Moreover, a large deletion of exons can benefit more affected population and recent progresses in genome editing , enabling the correction of the genetic mutations that are responsible for MD. The mainly gene editing approaches including exon skipping using antisense oligonucleotides, read-through of stop-codon mutations (e.g. PTC124, developed by PTC Therapeutics), and the CRISPR/Cas9-based genome editing technology to correct alterations in specific mutant genes.

Taking advantage of the extensive experience and advanced equipment, Creative Biolabs has developed various robust evaluation systems for gene therapy development in-house. We are proficient in every process of gene therapy to certainly accelerate the progress of your project. If you are interested in our service, please feel free to contact us for more information.

Reference

  1. Crispi, V. and Matsakas, A. (2018). Duchenne muscular dystrophy: genome editing gives new hope for treatment. Postgraduate Medical Journal, 94(1111), pp.296-304.
  2. Gene Therapy for Muscular Dystrophies: Progress and Challenges. Journal of Clinical Neurology, 6(3), p.111.
  3. Ramos, J. and Chamberlain, J. (2015). Gene therapy for Duchenne muscular dystrophy. Expert Opinion on Orphan Drugs, 3(11), pp.1255-1266.
  4. Chamberlain, J. and Chamberlain, J. (2019). Progress toward Gene Therapy for Duchenne Muscular Dystrophy.

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