Nonpeptide Polymers for Effective Delivery of PMO

One major concern that arises with the use of peptides as delivery enhancers is the immune response they might elicit, preventing from repeated administration and causing rejection of targeted tissues. This is particularly important as long-term repeated administrations are required for the treatment of DMD with antisense therapy. No signs of immune response were observed during the short-term treatment with the PPMOs (Wu et al. 2008) and previous reports also suggested the lack of...

DNA Vaccine

DNA vaccination has become the fastest growing field in vaccine technology following reports at the beginning of the 1990s that plasmid DNA induces an immune response to the plasmid-encoded antigen after intramuscular injection into mice (Wolff et al. 1990). In theory, this conceptually safe, non-live vaccine approach is a unique and simple way to induce not only humoral but also cellular immunity. Whereas traditional vaccines rely on the production of antibodies through the injection of live...

Mechanism of Immune Responses and Tolerance Induction

The immune system's reaction to antigen depends on (a) the relative frequencies of responding T and B cells and on the thresholds of the binding affinity that their receptors display, (b) the levels of antigen present, and (c) the period during which the antigen remains in secondary lymphoid tissue, where primary immune responses are initiated. For successful activation of naive T cells, signals derived by antigen-presenting cells (APCs) (Fig. 11.1) are required. The initial signal (Signal 1)...

The Therapeutic Threshold for Duchenne Cardiomyopathy Gene Therapy

Massons Trichrome Dmd

There is no doubt that 100 transduction is not possible with any gene therapy approach. Will partial transduction be therapeutically relevant In skeletal muscle, 20-60 dystrophin positive myofibers have been shown to increase muscle force in mdx mice (Liu et al. 2005 Watchko et al. 2002 Yoshimura et al. 2004). Encouragingly, patients with 50 mosaic expression in skeletal muscle were found to have mild muscle weakness (Arahata et al. 1989 Hoffman et al. 1988). Approximately 50 of the...

Dystrophinopathies

In 1987, the protein responsible for DMD, and its milder relative Beckers muscular dystrophy (BMD) was identified in humans and named dystrophin (Hoffman et al. 1987). DMD is an X-linked disease that typically presents itself early in childhood as muscle weakness and progresses to muscle loss and fibro-sis. Most boys with this disease die around the age of puberty or shortly thereafter from respiratory or cardiac failure. Dystrophin is a large cytoskeletal protein that is localized near the...

Muscle as the Target for Vaccine

The most common route of immunization used in DNA vaccine studies is the intramuscular route. Following intramuscular immunizations, the predominant cell type transfected with the DNA vaccines is myocytes (Danko et al. 1997 Wolff et al. 1990). However, muscle is not considered an immunologically relevant tissue as myocytes lack the characteristics of antigen-presenting cells (APCs) such as MHC-II expression, costimulatory molecules, or marked cytokine secretion. The insignificant role of muscle...

McArdle Disease

McArdle disease (Myophosphorylase deficiency GSD V) results from a deficiency in the muscle-specific isozyme of glycogen phosphorylase (PYGM). There exist 65 known mutations in the PYGM gene and although there is a great deal of genetic heterogeneity in the McArdle disease, it generally presents itself with clinical and biochemical homogeneity (Dimaur et al. 2002 McArdle 1951 Nogales-Gadea et al. 2007). McArdle disease was first described by Dr. Brian McArdle in 1951 after he evaluated a 30...

Adenoassociated Viral Vector for Vaccine Development

Adeno-associated viruses (AAVs) are non-pathogenic, transduce muscle cells well, and provide long lasting expression from primarily episomal molecular forms (Schnepp et al. 2003). As a non-enveloped virus, AAV exhibits high physical stability. Vectors derived from AAV have emerged as highly promising ones for use in gene therapy (Carter and Samulski 2000 Monahan and Samulski 2000). All virus-encoded genes are replaced with the gene of interest by flanking between the inverted terminal repeats...

Gene Therapy for Limb Girdle Muscular Dystrophies

Limb-girdle muscular dystrophies are a group of heterogeneous inherited neuro-muscular diseases caused by mutations in a number of different genes including genes encoding sarcoglycans SG a LGMD 2D , b LGMD 2E , g LGMD2C , and 8 LGMD 2F Lim and Campbell 1998 Hoffman 1999 . Sarcoglycans are small transmembrane proteins associated in equal stoichiometry on the muscle cell membrane to form a heterotetramer, termed the SG complex. Primary deficiency of any single SG protein generally results in...