Muscle Gene Therapy doc

[...]... failure Gene therapy for muscle diseases such as DMD requires efficient gene delivery to the striated musculature and specific, high-level expression of the therapeutic gene in a physiologically diverse array of muscles This can be achieved by the use of regulatory cassettes composed of enhancers and promoters that contain combinations of muscle- specific and ubiquitous Dongsheng Duan (ed.), Muscle Gene Therapy: ... Microdystrophin Gene for Duchenne Muscular Dystrophy Gene Therapy Takis Athanasopoulos, Helen Foster, Keith Foster, and George Dickson Abstract Duchenne muscular dystrophy (DMD) is a severe muscle wasting X-linked genetic disease caused by dystrophin gene mutations Gene replacement therapy aims to transfer a functional full-length dystrophin cDNA or a quasi micro/mini -gene into the muscle A number... Skeletal and Cardiac Muscles Charis L Himeda, Xiaolan Chen, and Stephen D Hauschka Abstract Gene therapy for muscular dystrophies requires efficient gene delivery to the striated musculature and specific, high-level expression of the therapeutic gene in a physiologically diverse array of muscles This can be achieved by the use of recombinant adeno-associated virus vectors in conjunction with musclespecific... partially characterized The muscle creatine kinase (MCK) gene has served as a useful model of muscle- specific gene transcription since its protein product is specifically and abundantly expressed in striated muscle, and its regulatory regions have been extensively characterized MCK is also expressed at different levels in different anatomical skeletal muscles, and in skeletal vs cardiac muscle (3, 4) This allows... 2 1 S D (1996) Analysis of muscle creatine kinase gene regulatory elements in skeletal and cardiac muscles of transgenic mice Mol Cell Biol 16, 1649–1658 Shield, M A., Haugen, H S., Clegg, C H., and Hauschka, S D (1996) E-box sites and a proximal regulatory region of the muscle creatine kinase gene differentially regulate expression in diverse skeletal muscles and cardiac muscle of transgenic mice Mol... constructed several generations of regulatory cassettes based on the enhancer and promoter of the muscle creatine kinase gene, some of which include heterologous enhancers and individual elements from other muscle genes Since the relative importance of many control elements varies among different anatomical muscles, we are aiming to tailor these cassettes for high-level expression in cardiac muscle, and in... expression of a reporter gene (13) (see Note 4) 8 Himeda, Chen, and Hauschka 2 Multimerize enhancers Multimerizing a single enhancer such as that from the MCK gene can provide significant increases in cassette activity (see Note 5) Tissue- or cell-type-specific enhancers from other striated muscle genes (such as the a-myosin heavy chain gene and the cardiac troponin T [cTnT] gene) can also be added... important for expression in particular muscle types In order to boost expression, new elements can be introduced Introduce additional positive control elements by site-directed mutagenesis (nucleotide mutation or insertion) These elements include general muscle elements (A/T-rich/MEF2, CArG/SRF, MCAT/TEF-1, MEF3/Six, NFAT), skeletal muscle elements (E-box), slow/ fast skeletal muscle elements (SURE/FIRE regions... activity in skeletal and cardiac muscle, and testing in mature muscle fiber cultures The basic principles described here can also be applied to engineering tissue-specific regulatory cassettes for other cell types Key words: Skeletal muscle, Cardiac muscle, Regulatory cassette, Muscular dystrophy, Gene therapy, Transcriptional regulation, Muscle creatine kinase 1 ntroduction I Duchenne muscular dystrophy... analyses of the muscle creatine kinase enhancer Trex control element in skeletal and cardiac muscle indicate differences in gene expression between muscle types Transgenic Res 12, 337–349 7 Bischoff, R (1989) Analysis of muscle regen1 eration using single myofibers in culture Med Sci Sports Exerc 21, S164–S172 8 Bischoff, R (1990) Interaction between satel1 lite cells and skeletal muscle fibers Development . incurable. Compared to retinal gene therapy, muscle gene therapy faces a number of unique challenges. Muscle is one of the most abundant tissues in the body. An effective therapy will require systemic. in mind, we compiled this collection of muscle gene therapy methods and protocols with the intention of bridging the translational gap in muscle gene therapy. The book is divided into three. survival, and physiology assays of skeletal muscle and heart function. Technology breakthroughs are the driving force in muscle gene therapy. Early muscle gene transfer studies were largely performed