Alternative strategies for gene therapy of hemophilia. Hematology Am Soc Hematol Educ Program 2010;2010:197-202
Date
01/18/2011Pubmed ID
21239794Pubmed Central ID
PMC3383974DOI
10.1182/asheducation-2010.1.197Scopus ID
2-s2.0-79955004711 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for "curing" hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome.
Author List
Montgomery RR, Shi QAuthors
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinQizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Coagulation Factors
Clinical Trials as Topic
Genetic Therapy
Hemophilia A
Humans
Mice