| For Immediate Release June 1, 2001 |
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SEATTLE (Thursday, May 31) -- Gutless adenovirus or "helper-dependent" adenovirus (HD-Ad), an adenoviral vector devoid of all adenoviral genes except for the packaging signal necessary for proper formation, is safe and effective for in vivo gene delivery to the liver, according to researchers at the American Society of Gene Therapy Annual Meeting.
Kazuhiro Oka and colleagues from Baylor College of Medicine, used HD-Ad to deliver the apolipoprotein E gene to mice null for the normal gene. Three different vectors were tested: a HD-Ad containing the nature apoE gene and its natural liver enhancer, a HD-Ad with the apoE cDNA and another liver gene promoter, and an earlier generation adenovirus containing apoE. The vectors were injected intravenously into apoE null mice, which were subsequently tested for plasma cholesterol and apoE levels.
Researchers found mice treated with the HD-Ad containing the normal gene had sharply decreased cholesterol and increased apo E levels, which have held for two years. The HD-Ad containing the cDNA also resulted in a dramatic response, but was gradually overcome. However, subsequent injection of an HD-Ad constructed from another adenovirus serotype had the same response, and the animals remain normal until present. Animals treated with the earlier generation adenovirus had a transient decrease in plasma cholesterol, but by 16 weeks it was back to control levels. In addition, there was a marked increase in liver enzyme using the earlier generation vector. Researchers concluded these observations support the feasibility and safety of HD-Ad vectors for clinical trials for long-term, high-level liver-targeted therapeutic gene expression.
Minigenes are sufficient in restoring form and function to dystrophic muscle
SEATTLE (Thursday, May 31) -- Among the many problems facing successful gene therapy is the ability to not only transfer a gene and have it expressed, but to have the encoded protein expressed at a therapeutic level and in a functional form. Two studies presented at the American Society of Gene Therapy Annual Meeting demonstrate that certain forms of the minigenes are sufficient to restore not only muscular architecture but also function. The studies, one from the University of Pittsburgh and the other from the Universities of Michigan and Washington, describe a series of elegant experiments aimed at overcoming Duchenne's Muscular Dystrophy (DMD) in a mouse model of the disease.
DMD, an X-linked genetic disease marked by progressive muscle degeneration that begins in the early teens and ends in death by the early 20s, is a result of mutations in the dystrophin gene. Dystrophin is a critical protein component of muscle structure and function, and the gene encoding it is large, spanning 3 million base pairs on the X chromosome. Even the cDNA of the naturally expressed dystrophin gene is about 14kb in length, far too large for the best skeletal muscle gene therapy vector available (adeno-associated virus or AAV, which can carry gene inserts of up to 5kb).
In the first study, Scott Harper of the University of Washington, School of Medicine and colleagues from the University of Michigan Medical School previously altered the dystrophin gene, removing sections of it thought to be "non-essential," in order to make a "mini" or "micro" dystrophin gene of about 4.6kb in length that could be efficiently packed and delivered to the muscle using AAV. Despite the success at delivery and apparent repair of damaged muscle in a mouse model of DMD, researchers found it to be unclear whether or not the mini-dystrophins have enough information to functionally repair the muscle, i.e., to restore normal contractile properties.
In the second study, Bing Wang and colleagues from the University of Pittsburgh School of Medicine and Harper and colleagues set out to assay the mini-dystrophin gene using two separate approaches. Using AAV as a delivery vehicle, Harper and colleagues inserted the new genes into the hind limb muscles of mice already showing pathological signs of disease. By contrast, Wang and colleagues created minidystrophin transgenic mice (i.e., mice that had the new genes inserted in the embryo stage, and thus incorporated into all cells of the body).
The American Society of Gene Therapy is the largest medical professional organization representing researchers and scientists dedicated to discovering new gene therapies. ASGT was established in 1996, and has grown to more than 3,000 members. It is committed to promoting and fostering the general field of research involving gene therapy and to promoting professional and public education in all areas of gene therapy.
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