The clinical trial reported in NEJM “builds on prior work and on encouraging pre-clinical data in non-human primates,” states VandenDriessche and coauthor of the commentary with Marinee Chuah, PhD, Department of Gene Therapy & Regenerative Medicine, Free University of Brussels and the Center for Molecular and Vascular Biology, University of Leuven, Belgium. It demonstrated that injection of an adeno-associated virus (AAV) vector carrying the gene for the clotting factor FIX into patients with severe hemophilia B led to efficient delivery of the gene into liver cells and sufficient production of the FIX protein to transform the disease from severe to a moderate or mild form of hemophilia, although it does not represent a cure. This effect has been stable and has eliminated or substantially reduced the need for the patients to receive standard protein replacement, which is cumbersome and expensive. Substantial improvements in vector technology set the stage for this success; these included a self-complementary genome to increase efficiency pioneered by R. Jude Samulski, PhD, Director, Gene Therapy Center, University of North Carolina at Chapel Hill, and the use of a novel AAV capsid from a natural rhesus monkey isolate called AAV8, which was discovered and developed by James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy and Human Gene Therapy Methods, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Recently published articles in Human Gene Therapy document the development and optimization of the AAV vectors used to deliver the FIX gene in this clinical trial. Two key papers are:
• Allay JA, et al. Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial. (http://www.liebertonline.com/
• Fagone P, et al. Systemic errors in quantitative PCR titration by self-complementary AAV vectors and improved alternative methods. (http://www.liebertonline.com/
“The successful treatment of patients with hemophilia B with gene therapy is a landmark event representing the culmination of over 20 years of work by many laboratories,"
Human Gene Therapy and HGT Methods, the Official Journal of the European Society of Gene and Cell Therapy, British Society for Gene Therapy, French Society of Cell and Gene Therapy, German Society of Gene Therapy, and five other gene therapy societies is the authoritative peer-reviewed journal published 18 times per year in print and online. Human Gene Therapy presents reports on the transfer and expression of genes in mammals, including humans. Related topics include improvements in vector development, delivery systems, and animal models, particularly in the areas of cancer, heart disease, viral disease, genetic disease, and neurological disease, as well as ethical, legal, and regulatory issues related to the gene transfer in humans. Tables of contents and a free sample issue may be viewed online at www.liebertpub.com/
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