Background alzheimers Shape Background alzheimers Shape Background alzheimers Shape
Grants > Regulation of NGF Expression by Oligonucleotides Updated On: Jan. 19, 2025
Alzheimer's Disease Research Grant

Regulation of NGF Expression by Oligonucleotides

BFF logo

Principal Investigator

Brad Wise, PhD

Icahn School of Medicine at Mount Sinai

New York, NY, USA

About the Research Project

Program

Alzheimer's Disease Research

Award Type

Standard

Award Amount

$75,000

Active Dates

April 01, 1995 - June 30, 1996

Grant ID

A1995060

Summary

Nerve growth factor (NGF) is a protein essential for the survival, development and maintenance of sensory and sympathetic neurons in the peripheral nervous system and of basal forebrain cholinergic neurons in the central nervous system (CNS). In the CNS, NGF expression is highest in brain areas involved with learning and memory functions. The results of many in vitro and in vivo studies have led to the suggestion that NGF administration may be beneficial in counteracting the cholinergic neurodegeneration characteristic of Alzheimer’s disease. Indeed, the first clinical trial of NGF infusion to an Alzheimer patient yielded some transient and long-lasting benefits, and clinical trials with NGF are continuing. Given the neurotrophic action of NGF toward cholinergic neurons and its potential to prevent or delay the accelerated loss of these neurons in Alzheimer’s disease, the central issue becomes how to administer or increase brain levels of NGF. Approaches to a therapeutic role for NGF could potentially include (i) the direct intracerebral administration of NGF, (ii) the transplantation into brain of genetically engineered cells which produce NGF, (iii) gene therapy using viral vectors containing the NGF gene, and (iv) the development of pharmacological agents which enhance the brain production of endogenous NGF. This last approach is the subject of this research proposal.

NGF is synthesized from a specific messenger ribonucleic acid (mRNA) sequence. Based on  studies demonstrating that NGF mRNA degradation, which plays a significant role in the overall control ofNGF expression, is regulated by an instability determinant in the 3′-untranslated region (3’UTR) of the mRNA, we hypothesize that this region of the mRNA may be a site for pharmacological interventions designed to enhance cellular NGF production. The objective of this research proposal is to determine whether oligoribonucleotides (oligoRNAs) derived from the 3′-UTR of the mRNA can stabilize NGF mRNA by blocking the activity of the instability determinant or by sequestering factors which degrade the mRNA. Such a blockade might increase NGF production in neuronal and astroglial cells. The specific aims, then, are (1) to identify oligoRNA probes which stabilize NGF mRNA in a cell-free RNA decay system, (2) to examine whether the identified oligoribonucleotide probes will increase NGF expression in cultures of brain neurons and astrocytes, and (3) to transfect an astroglioma cell line with vectors designed to express the biologically active oligoRNAs to see if cellular synthesis of small regulatory RNA molecules will lead to enhanced NGF production.

The results of this research project should provide convincing evidence for, or against, the use of novel RNA-derived molecules as cellular inducers of NGF expression in neurons and glial cells. Moreover, new pharmacotherapies could be envisioned using these oligoRNA molecules in the treatment of Alzheimer’s disease. Since oligoRNAs may not cross the blood-brain-barrier, this approach will have to be linked to the development of methods to deliver macromolecules across this barrier, as is being pursued by other investigators. Also, genetically engineered vectors are being developed to directly transduce and express the NGF gene in neurons and glial cells as one form of gene therapy for Alzheimer’s disease, and potentially for other neurodegenerative disorders as well. These same gene transfer vectors could be used to direct the expression of those RNA sequences which stimulate endogenous NGF production in brain cells. Thus, the long range goal is to integrate the results of this research project with those of other studies to develop a novel and effective pharmacological or gene therapy-based treatment for Alzheimer’s disease.