Adeno-associated virus vectors for therapeutic gene transfer.

Adeno-associated virus (AAV) is currently being used in several human gene therapy trials, including one targeting hemophilia B and another targeting cystic fibrosis, and to date has demonstrated persistent expression without inflammation of the target tissue. Some of the unique features that have distinguished AAV from other gene therapy vectors include (i) its ability to transduce both dividing and non-dividing cells; (ii) its broad tropism; (iii) its ability to integrate into a host chromosome or persist episomally, creating the potential for long-term expression; (iv) its status as a nonpathogenic virus; and (v) the lack of a cellmediated immune response. AAV vectors have successfully transduced many types of tissue including eye (34), muscle (56), liver (63), neurons (16), hematopoietic progenitors (59), gut (22), and keratinocytes (5). Therapeutic genes expressed by AAV vectors include factor IX (10,37,40,43,63), factor VIII (8), cystic fibrosis gene (CFTR) (27), brain-derived neurotrophic factor (23,42), glial cell line-derived neurotrophic factor (GDNF) (41,46,47), and glutamic acid decarboxylase (45), among others. Many exciting advances in the AAV field have occurred recently, directly impacting its utility in therapeutic gene delivery, including the development of vectors using alternative AAV serotypes, modification of the current capsids to allow either more restricted targeting of cells or a broader tropism, creative packaging strategies allowing portions of genes to be packaged in different viruses and overcoming the limited packaging capacity of AAV vectors, and alternative DNA packaging strategies overcoming one of the rate-limiting steps of transgene expression.