Gene Therapy for Alzheimer's Disease Clinical Trial

2014-08-27 03:56:49 | BioPortfolio


This Phase I clinical trial is the first step in testing gene therapy. This study is called a "Safety/Toxicity" study by the Food and Drug Administration, and primarily aims to determine whether the experimental protocol is safe for humans. It will determine whether the study procedure causes side effects in humans, and may also give us a preliminary sense of whether this will be effective in combating Alzheimer's disease in humans.


Although the precise pathogenesis of AD is unknown, certain pathological features accompany the disease. These pathological features include the abnormal accumulation of extracellular amyloid, the formation of intraneuronal neurofibrillary tangles, synapse loss, and cellular degeneration. Cellular degeneration occurs in several neuronal populations in the central nervous system. Among the neuronal populations that degenerate in AD, loss of basal forebrain cholinergic neurons is particularly severe. Loss of cholinergic neurons in AD correlates best with severity of dementia, the density of amyloid plaques in the brain, and the amount of synapse. To date, the only FDA-approved therapies for Alzheimer's Disease focus on augmenting the function of degenerating cholinergic neurons.

The present trial will move beyond compensating for cholinergic neuronal degeneration by attempting to 1) protect cholinergic neurons from degeneration, and 2) augment the function of remaining cholinergic neurons by directly elevating choline acetyltransferase (ChAT) function in neurons. These two therapeutic interventions will be brought about by the delivery of human NGF to the brain.

NGF has been shown to prevent both lesion-induced and spontaneous, age-related degeneration of basal forebrain cholinergic neurons. Further, NGF infusions reversed both lesion-induced memory loss and spontaneous, age-related memory loss in rodents. Based on these findings, NGF administration offers significant potential as a neuroprotective strategy in Alzheimer's disease.

Grafts of primary fibroblasts transduced to express human nerve growth factor have been shown to sustain NGF in vivo gene expression for at least eighteen months in the rodent central nervous system. In addition, these grafts sustain NGF messenger RNA production for at least 14 months in vivo. In primate systems, ex vivo NGF gene therapy has been demonstrated to sustain NGF protein production in the brain in the rhesus money for at least one year.

Thus, the available data suggests that ex vivo NGF gene therapy is an effective means of preventing loss of basal forebrain cholinergic neurons and of augmenting cholinergic function in the primate brain. In animals, this procedure is safe and well tolerated. Based on these data, clinical trials of ex vivo NGF gene therapy in Alzheimer's disease has begun.

This is an 18 month, open label, prospective Phase I clinical trial of Ex Vivo Gene Therapy for Alzheimer's disease in 8 patients with a mild degree of cognitive impairment. Patients will be screened for the diagnosis of Probable Alzheimer's disease of mild severity. After obtaining informed consent, three skin biopsies will be obtained to generate cultures of primary, autologous fibroblasts. These cells will be cultured, then genetically modified to produce and secrete the human nerve growth factor (NGF) molecule. If fibroblasts are deemed acceptable based on NGF production rates and standard cell culture sterility tests, then patients will receive intracerebral injections of their own primary fibroblasts into the region of basal forebrain cholinergic neurons in the brain, where neurons are undergoing atrophy as a result of Alzheimer's disease.

Study Design

Control: Uncontrolled, Endpoint Classification: Safety Study, Masking: Open Label, Primary Purpose: Treatment


Alzheimer Disease


Human Nerve Growth Factor


University of California, San Diego, ADRC
La Jolla
United States




National Institute on Aging (NIA)

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:56:49-0400

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Medical and Biotech [MESH] Definitions

NERVE GROWTH FACTOR is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity.

Cell surface receptors that bind NERVE GROWTH FACTOR; (NGF) and a NGF-related family of neurotrophic factors that includes neurotrophins, BRAIN-DERIVED NEUROTROPHIC FACTOR and CILIARY NEUROTROPHIC FACTOR.

A fibroblast growth factor that preferentially activates FIBROBLAST GROWTH FACTOR RECEPTOR 4. It was initially identified as an androgen-induced growth factor and plays a role in regulating growth of human BREAST NEOPLASMS and PROSTATIC NEOPLASMS.

A low affinity receptor that binds NERVE GROWTH FACTOR; BRAIN-DERIVED NEUROTROPHIC FACTOR; NEUROTROPHIN 3; and neurotrophin 4.

A single-chain polypeptide growth factor that plays a significant role in the process of WOUND HEALING and is a potent inducer of PHYSIOLOGIC ANGIOGENESIS. Several different forms of the human protein exist ranging from 18-24 kDa in size due to the use of alternative start sites within the fgf-2 gene. It has a 55 percent amino acid residue identity to FIBROBLAST GROWTH FACTOR 1 and has potent heparin-binding activity. The growth factor is an extremely potent inducer of DNA synthesis in a variety of cell types from mesoderm and neuroectoderm lineages. It was originally named basic fibroblast growth factor based upon its chemical properties and to distinguish it from acidic fibroblast growth factor (FIBROBLAST GROWTH FACTOR 1).

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