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

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Handbook of Neurochemistry and Molecular Neurobiology

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Abstract:

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, adeno‐associated 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.

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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

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Acknowledgments

Gene therapy projects for neurological diseases are funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant 1R01 NS44556.01 and National Institute of Diabetes and Digestive and Kidney Diseases 1 RO3 TW006273-01 to M.G.C.; National Institutes of Health/National Institute of Neurological Disorders and Stroke Grants 1 RO1 NS 42893.01, U54 NS045309-01, and 1R21 NS04729-01 and Bram and Elaine Goldsmith Chair In Gene Therapeutics to P.R.L.; and the Linda Tallen & David Paul Kane Annual Fellowship to M.G.C. and P.R.L. We also thank the generous funding our institute receives from the Board of Governors at Cedars Sinai Medical Center. We thank the support and academic leadership of S. Melmed, and R. Katzman and D. Meyer for their superb administrative and organizational support.

Authors
  1. P. R. Lowenstein
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  2. K. Kroeger
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  3. C. Barcia
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  4. J. Zirger
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  5. D. Larocque
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  6. M. G. Castro
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, 10962, New York, Orangeburg, USA

    Abel Lajtha (Director) (Director)

  2. The Buniatian Institute of Biochemistry the National Academy of Sciences, 5/1 Sevag str., 375014, Yerevan, Republic of Armenia

    Armen Galoyan

  3. Dept. Immunophysiology Medical Faculty, Inst. of Normal and Pathological Physiology, Deutschhausstrase 2, D–35037, Marburg, Germany

    Hugo O. Besedovsky

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Lowenstein, P.R., Kroeger, K., Barcia, C., Zirger, J., Larocque, D., Castro, M.G. (2008). Evolutionary Origins of the Brain's Immune Privilege. Implications for Novel Therapeutic Approaches: Gene Therapy. In: Lajtha, A., Galoyan, A., Besedovsky, H.O. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30398-7_11

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