Gene Therapy for Hemophilia B: Aav-Mediated Transfer of The Gene for Coagulation Factor IX to Human Muscle
Hemophilia B is an X-linked bleeding disorder caused by a deficiency of coagulation factor IX. In its severe form, the disease results in spontaneous bleeding as well as bleeding following surgery or trauma, and is clinically indistinguishable from hemophilia A (factor VIII deficiency). The major morbidity of the disease is the chronic arthropathy of hemophilia that develops following spontaneous hemorrhage into the joint spaces. Blood in the joint space serves as an irritant causing proliferation of the vascular synovial membranes. Hypertrophied synovium is more susceptible to injury resulting in a vicious cycle of rebleeding that furthers the destruction of the joint. The major bleeding-related mortality of hemophilia is intracranial hemorrhage that occurs in between 3 and 14% of patients (1, 2, 3). The mortality rate from intracranial hemorrhage ranges from 20–50%, and survivors are often left with severe neurological sequelae such as seizures, paresis or mental retardation (1). Current treatment of hemophilia is based on the episodic intravenous infusion of highly purified plasma-derived or recombinant clotting factor concentrates in response to bleeding episodes (on-demand therapy).
KeywordsToxicity Hepatitis Recombinate Bilirubin Creatine
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- 6.Lyon DJ, Chapman CS, Martin C, Brown KE, Clewley JP, Flower AJE and Mitchell VE. Symptomatic parvovirus B19 infection and heat-treated factor IX concentrate. (letter). Lancet 1:1985, 1989.Google Scholar
- 7.Laurian Y, Dussaix E, Parquet A, Chalvon-Demersay A, d’Oiron R and Tchemia G. Transmission of human parvovirus B19 by plasma derived factor VIII concentrates. Nouv Rev Fr Haematol 36:449–453, 1994.Google Scholar
- 9.Linnen I, Wages Jr J, Zhang-Keck Z-Y, Fry K, Krawczynski K, Alter H, Koonin E, Gallagher M, Alter M, Hadziyannis S, Karayiannis P, Fung K, Nakatsuji Y, Shih JW-K, Young L, Piatak Jr. M, Hoover C, Fernandez J, Chen S, Zou J-C, Morris T, Hyams K, Ismay S, Lifson J, Hess G, Foung S, Thomas H, Bradley D, Margolis H and Kim J. Molecular cloning and disease association of hepatitis G virus: A transfusion-transmissible agent. Science 271:505–508, 1996.PubMedCrossRefGoogle Scholar
- 11.Snyder E and Lipton K. Association Bulletin 94–4--Hepatitis G virus: status report and assessment of clinical relevance. AABB News Briefs August 1998:20–21, 1998.Google Scholar
- 16.Snyder R, Xiao X and Samuiski R. Production of recombinant adeno-associated viral vectors in N. e. a. Dracopoli. Current Protocols in Human Genetics. New York, John Wiley & Sons. 1–24. 1996.Google Scholar
- 19.Herzog R, Yang E, Couto L, Hagstrom J, Elwell D, Fields P, Burton M, Bellinger D, Read M, Brinkhous K, Podsakoff G, Nichols T, Kurtzman G and High K. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nature Medicine 5:56–63, 1999.PubMedCrossRefGoogle Scholar
- 20.Tawa N and Goldberg A. Myology. New York, McGraw-Hill, Inc. 1994.Google Scholar
- 22.Bray GL, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-Johnson M, Shapiro A, Scheibel E, White G and Lee M. A multicenter study of recombinant factor VIII (recombinate): Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 83:2428–2435, 1994.PubMedGoogle Scholar