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Growth Factor Gene Therapy for Alzheimer Disease

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Growth Factor Gene Therapy for Alzheimer Disease Neurosurg Focus 13 (5):Article 5, 2002, Click here to return to Table of Contents Growth factor gene therapy for Alzheimer disease MARK H. TUSZYNSKI, M.D., PH.D., HOI SANG U, M.D., JOHN ALKSNE, M.D., ROY A. BAKAY, M.D., MARY MARGARET PAY, R.N., DAVID MERRILL, PH.D., AND LEON J. THAL, M.D. Departments of Neurosciences and Surgery, Division of Neurosurgery, University of California at San Diego, La Jolla; Veterans Administration Medical Center, San Diego, California; and Department of Surgery, Division of Neurosurgery, Rush–Presbyterian Medical Center, Chicago, Illinois The capacity to prevent neuronal degeneration and death during the course of progressive neurological disorders such as Alzheimer disease (AD) would represent a significant advance in therapy. Nervous system growth factors are families of naturally produced proteins that, in animal models, exhibit extensive potency in preventing neuronal death due to a variety of causes, reversing age-related atrophy of neurons, and ameliorating functional deficits. The main challenge in translating growth factor therapy to the clinic has been delivery of growth factors to the brain in sufficient concentrations to influence neuronal function. One means of achieving growth factor delivery to the central nervous system in a highly targeted, effective manner may be gene therapy. In this article the authors summarize the develop- ment and implementation of nerve growth factor gene delivery as a potential means of reducing cell loss in AD. KEY WORDS • Alzheimer disease • basal forebrain cholinergic system • gene therapy • nerve growth factor Alzheimer disease is the most common neurodegenera- the entire neocortex and hippocampus, leads to the loss of tive disorder, afflicting approximately 4 million people in acetylcholine, which in turn is thought to exacerbate sig- the United States. This number will exceed 14 million by nificantly the “cortical” dementia in AD.2 Cholinergic sys- the year 2050. At a current cost of $100 billion per year, tems modulate activity in target hippocampal and cortical AD is an imminent epidemic that threatens to severely regions,16 a mechanism that is thought to be responsible strain the healthcare system unless effective therapies are for the impairment in cognition when these cholinergic developed.32 Alzheimer disease accounts for the majority inputs are lost. Indeed, cholinergic neuronal degeneration of dementia cases, with chief features of memory loss and has been shown to correlate with clinical severity, density dysfunction of at least one other higher cortical function. of amyloid plaques, and the loss of synapses in AD.2,9 In the late stage of the disease, profound loss of memory Thus, therapies targeted at ameliorating or preventing dys- and executive function occurs, rendering individuals inca- function of cholingeric neurons could affect cognitive de- pable of self care. With disease progression, there is pro- cline in AD. To date, the only therapeutic agents approved found degeneration of cortical neurons in frontal, parietal, by the Federal Drug Administration for the treatment of and temporal neocortices but relative sparing of primary AD are the AChE inhibitors, which augment acetylcho- sensory and motor cortices. line levels in the brain.34 Cholinesterase inhibitors, how- Extensive degeneration of subcortical neuronal popula- ever, exert only modest effects on symptoms of AD. It is tions also occurs in AD, including cholingeric, serotoner- gic, and noradrenergic systems. By the midstages of AD, thought that this occurs because the degeneration of the for example, significant degeneration of the subcortical BFC system continues unabated during treatment with BFC system has occurred, a cell population that includes AChE inhibitors, eventually leading to inadequate cholin- the nucleus basalis of Meynert. This degeneration of the ergic compensation. Further, the doses of orally adminis- cholinergic system, which projects extensively throughout tered cholinesterase inhibitors that can be administered are limited because of the development of peripheral side ef- fects. Hence, the therapeutic potential of fully augmenting Abbreviations used in this paper: AChE = acetylcholinester- cholinergic function in AD cannot entirely be tested with ase; AD = Alzheimer disease; BFC = basal forebrain cholinergic; currently available oral cholinesterase medications. CNS = central nervous system; ICV = intracerebroventricular; Novel therapies that target neuronal loss in AD should NGF = nerve growth factor; NTF = neurotophic factor. not only aim to augment neuronal function but ideally Neurosurg. Focus / Volume 13 / November, 2002 1 Unauthenticated | Downloaded 09/26/21 11:41 PM UTC M. H. Tuszynski, et al. should also prevent cell loss. Nervous system growth human NGF were reported to prevent degeneration of factors, or NTFs, long known to promote survival and BFC neurons in primates.24,41 function of distinct neuronal populations during nervous Thus, by 1991 substantial evidence derived from rodent system development, are a class of molecules that might and primate models suggested that NGF delivery might achieve these objectives in neurodegenerative disorders. be a logical means of attempting to ameliorate choliner- To date, more than 100 NTFs have been identified in the gic cell loss in AD. Indeed, ICV infusion of NGF was CNS. Most can be grouped into distinct “families” of re- attempted in three AD patients in Sweden.15 Whereas lated growth factors based on common structures and sig- Mini-Mental Status Examination scores (a simple mea- naling mechanisms. The first NTFs to be discovered, and sure of cognitive function) did not improve after NGF the most thoroughly studied to date, is the “classic neu- infusions, transient increases in scores were seen on some rotrophin” family consisting of NGF, brain-derived NTF, episodic memory tests and there was some evidence of neurotrophin–3, and neurotrophin–4/5. Nerve growth fac- improved physiological parameters of brain function, in- tor is the prototypical member of the classic neurotrophin cluding nicotine binding, cortical blood flow, and electro- family, and is a specific survival factor for BFC neurons. encephalographic activity. The trial, however, was dis- It is produced throughout life by neurons in the hippo- continued after the onset of debilitating side effects due campus and neocortex, secreted extracellularly, and then to NGF infusion. In particular, back pain developed in bound by specific receptors on cholinergic axon terminals patients within 2 to 14 days after the onset of ICV NGF in target regions.12,21,22 It is then retrogradely transported to infusions. Pain was hypothesized to result from NGF dif- the cholinergic cell body. Nerve growth factor also acts fusing throughout the cerebrospinal fluid and reaching locally on the axon terminal via NGF receptor–mediated nociceptive NGF-responsive cell bodies in the dorsal tyrosine kinase signaling pathways. Collectively through horns and dorsal root ganglia. In addition, weight loss these receptor mechanisms, NGF modulates the function occurred, likely due to NGF-mediated activation of satiety of BFC neurons during development and throughout adult centers in the hypothalamus. Notably, the authors of pre- life in a manner that is as yet incompletely understood. vious animal studies reported that whereas ICV NGF in- Notably, levels of NGF protein are diminished in BFC fusions successfully rescued degenerating cholinergic neurons in the brains of patients with AD,31,37 although its neurons, these infusions also induced weight loss,45 sym- production by the cortex and hippocampus is not altered, pathetic axon sprouting around cerebral vasculature,36 and suggesting that deficient NGF transport to cholinergic migration and expansion of Schwann cells into a thick cel- neurons may cause or contribute to the loss of this cell lular layer surrounding the medulla and spinal cord.14,46 population.10 The finding in animal models that NGF de- These findings prohibited the initiation of further clinical livery to the adult brain can ameliorate cholinergic cell trials involving ICV infusions of NGF. Thus, whereas loss and reverse cholinergic atrophy with aging has led to NGF treatment offered substantial potential as a means a focus on NGF delivery as a potential therapy for AD. of reducing cholinergic cell loss in AD, an alternative For reasons to be presented, however, safe NGF delivery method of delivery was required to deliver sufficient NGF requires specific targeting to the BFC system. Gene ther- doses to basal forebrain regions while restricting NGF apy is one means of achieving localized, targeted, and spread to other sensitive neuronal populations of the hypo- restricted delivery of NGF into the brain and is the subject thalamus, brainstem, and spinal cord. of a current Phase I clinical trial in AD. GENE DELIVERY OF NGF NERVE GROWTH FACTOR EFFECTS IN THE ADULT BRAIN One approach to the specific delivery of NGF to cholin- ergic neurons of the basal forebrain is gene therapy. In Nerve growth factor was serendipitously discovered in general, there are two forms of gene therapy: ex vivo and 1951 by Levi-Montalcini and Hamburger29 in the course in vivo gene therapy. In ex vivo gene therapy, cells are of in vitro experiments in which they examined properties genetically modified in vitro to express a gene of interest, of a sarcoma cell line. Subsequently NGF was discovered and are then implanted into the brain where they in effect to be an essential survival
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