By Janice Staber, MD

Since I was little, I’ve been surrounded by scientific intrigue. One of my first memories of the idea of moving genetic material into a person was from my early high school days. When discussing gene transfer, a classmate asked, “So, we could make people blue by moving the gene that makes birds blue into a human?” This was met by a classroom full of laughter, but then he continued, “Seriously, does this mean we can correct human diseases with good genes?” At that time, I was skeptical that this was possible, but that interaction planted a seed of hope that we could someday find cures for diseases using these methods.

 Hemophilia A and hemophilia B are inherited disorders characterized by deficiencies in factor VIII and factor IX, respectively. It is an exciting time in the world of hemophilia as there has been considerable progress in the development of hemophilia therapeutics over the last several decades. New developments include extended half-life replacement factor proteins, RNA interference to balance the clotting cascade, and factor VIII mimetics. How- ever, most exciting is the development of gene therapy. Amit Nathwani, MD, PhD, of University College London is equally interested in the cure of disease. Currently, marketed hemophilia therapies are not curative, not available worldwide, and can leave patients with chronic hemarthopathy. Nathwani will present his work in this exciting area at the Ham-Wasserman Lecture on Saturday at 12:45 p.m. (Hall D, Level 2, Orange County Convention Center – map it). Adeno-associated viral vectors (AAV) are non- pathogenic and mostly nonintegrating, have a limited packaging capacity of 5kb, are devoid of wild-type coding sequences, and can be delivered either in vivo or ex vivo. AAV was cloned and recombinant AAV was produced in the 1980s to early 1990s. AAV vector development including tissue tropism, liver-specific promoters, codon-optimization, self-complementary sequence, and manufacturing techniques excelled during the 1990s and 2000s.

Nathwani’s journey started in 1997 with a clinical fellowship in the laboratory of Arthur Nienhuis, MD, where he investigated “the regulation of tissue factor gene in endothelial cells.” This work made him “wonder how and if we could use the gene transfer approach to deliver therapeutic genes to patients as an alternative to the palliative approaches that were being used at the time in most monogenetic disorders.” The journey was a winding road that included successes and setbacks. A major achievement came in 2010 with the recruitment of six patients with hemophilia B to receive gene therapy with an AAV. Four of the six patients stopped using prophylactic factor VIII and have had a stable durable expression for up to eight years. The disease burden of these patients was significantly reduced and the results awe inspiring.

This pivotal trial demonstrated the potential for a cure in hemophilia. However, subgroups of patients were not eligible for the study, including children, those with inhibitors, patients with AAV antibodies, and patients with hepatitis or HIV. Also excluded were other patient populations from clinical gene therapy trials, including those with chronic diseases such as diabetes, hypertension, a history of malignancy, and active or chronic infections. This leads us to ponder the future of gene therapy.

Dr. Nathwani will share with us the advancements in hemophilia gene therapy and discuss the steps needed to develop gene therapy more broadly. Dr. Nathwani is most excited that “gene therapy has enabled individuals to enjoy a much fuller life than had been possible when they were on factor replacement therapy. Despite being able to do more, these patients bleed less frequently and therefore, gene therapy provides an important paradigm shift for patients with inherited bleeding disorders.” Dr. Nathwani wants to highlight that “after decades of failure, gene therapy has finally begun to have an impact in pa- tients with inherited diseases as well as those with malignancies. However, there are many unanswered questions, and this field will continue to develop in time with further advances in science.”

Dr. Staber indicated no relevant conflicts of interest.

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