11 Evolutionary Origins of the Brain's Immune Privilege. Implications for Novel Therapeutic Approaches: Gene Therapy

Researchers have conducted numerous pre-clinical and clinical gene transfer studies using recombinant viral vectors modified from a wide range of pathogenic viruses such as adenovirus, adenoassociated virus, herpes simplex 1 virus, and lentivurus. Herein, we examine the utility of each vector system to treat disorders of the nervous system as well as offer a summary of various strategies and clinical outcomes of gene therapy approaches to treat neurological disorders such as Parkinson’s disease, Alzheimer’s disease, and glioma. As viral vectors are derived from pathogenic viruses, they have an inherit ability to induce a vector specific immune response. The role of the immune response against the viral vector gene delivery vehicle has been implicated in the inconsistent and unpredictable translation of pre-clinical success into therapeutic efficacy in human clinical trials using gene therapy to treat neurological disorders. The effects of the innate and adaptive immune responses on therapeutic gene expression mediated by viral vectors are discussed. Furthermore, the immune responses against gene therapy vectors and the resulting loss of therapeutic gene expression are examined in the context of the architecture and neuroanatomy of the brain immune system. List of Abbreviations: AAV, adeno‐associated virus; APCs, antigen‐presenting cells; BBB, blood–brain barrier; BDNF, brain‐derived neurotrophic factor; CAR, coxsackievirus–adenovirus receptor; CNTF, ciliary neurotrophic factor; CTLs, cytotoxic T cells; DC, dendritic cells; DIC, disseminated intravascular coagulation; GBM, glioblastoma multiforme; GDNF, glial‐derived neurotrophic factor; GFAP, glial fibrillary acidic protein; HD, Huntington disease; HPRT, hypoxanthine–guanine phosphoribosyltransferase; HSV, herpes simplex virus; IRFs, interferon regulatory factors; ITR, inverted terminal repeats; LNS, Lesch–Nyhan syndrome; MAPK, mitogen‐activated protein kinase; MS, multiple sclerosis; NGF, neural growth factor; NK, natural killer; NKT, natural killer T; PI‐3K, phophoinositide‐3‐OH kinase