Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMD rat model.

Duchenne muscular dystrophy (DMD) is a muscle wasting disorder caused by mutations in the gene encoding dystrophin. Gene therapy using micro-dystrophin (MD) transgenes and recombinant adeno-associated virus (rAAV) vectors hold great promise. To overcome the limited packaging capacity of rAAV vectors, most MD do not include dystrophin carboxy-terminal (CT) domain.

Dose-Dependent Microdystrophin Expression Enhancement in Cardiac Muscle by a Cardiac-Specific Regulatory Element.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1:5,000 live male births and is characterized by muscle wasting. By the age of 13 years, affected individuals are often wheelchair bound and suffer from respiratory and cardiac failure, which results in premature death. Although the administration of corticosteroids and ventilation can relieve the symptoms and extend the patients' lifespan, currently no cure exists for DMD.

Context-Dependent IL-1 mRNA-Destabilization by TTP Prevents Dysregulation of Immune Homeostasis Under Steady State Conditions.

The bioavailability of the major pro-inflammatory cytokines IL-1α and IL-1β is tightly controlled by transcription and post-translational processing to prevent hyperinflammation. The role of mRNA decay in maintenance of physiological IL-1 amounts remained unknown. Here we show that the down-regulation of and mRNA by the mRNA-destabilizing protein TTP (gene ) is required for immune homeostasis.

Chimeric Trojan Protein Insertion in Lentiviral Membranes Makes Lentiviruses Susceptible to Neutralization by Anti-Tetanus Serum Antibodies.

This study describes the initial testing of a novel strategy for neutralization of lentiviruses using the fundamental biology of enveloped viruses' assembly and budding. In the field of gene therapy, viral vector surface proteins have been manipulated in order to redirect host cell specificity by alteration of pseudo-types. This study tested whether known viral pseudo-typing proteins or surface proteins known to be recruited to the human immunodeficiency virus (HIV) envelope could be engineered to carry neutralizing epitopes from another microorganism onto the lentiviral surface.

Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles.

In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma.

Adeno-Associated Virus (AAV) Mediated Dystrophin Gene Transfer Studies and Exon Skipping Strategies for Duchenne Muscular Dystrophy (DMD).

Duchenne muscular dystrophy (DMD), an X-linked inherited musclewasting disease primarily affecting young boys with prevalence of between1:3,500- 1:5,000, is a rare genetic disease caused by defects in the gene for dystrophin. Dystrophin protein is critical to the stability of myofibers in skeletal and cardiac muscle. There is currently no cure available to ameliorate DMD and/or its patho-physiology.