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Design of a gene therapy for Alzheimer's disease using superior stabilizing tubulin molecules

Parole chiave GENE EXPRESSION DATA ANALYSIS, GENE THERAPY, AD

Riferimenti MARCO AGOSTINO DERIU, BARBARA ONIDA, JACEK ADAM TUSZYNSKI

Gruppi di ricerca 28- biomedica

Descrizione Alzheimer’s disease (AD) presents with two major pathologies—neurofibrillary tangles and senile plaques—and several neurochemical imbalances. Current FDA-approved treatments target the neurochemical imbalances, but as is widely known, these approaches provide only modest clinical improvements and do not halt progression of the disease. Despite numerous clinical trials addressing myriad targets in AD brain, virtually none yet attempted seem to produce the robust results needed to effectively treat the large and growing population of AD patients. In this project we will provide a novel treatment strategy to directly protect against the pathology cascade underlying AD by fortifying brain microtubules in damaged regions of Alzheimer’s disease brain. A growing literature supports the contention that microtubules are a central issue in AD pathology. Rationale molecular drug design allows scientists to alter the structure of targeted proteins in silico and test the effects of drug binding on those targets. Our research focuses on how microtubules change structural conformation upon drug binding. We present here several altered structures of tubulin that produce more structurally stable microtubules. Increasing microtubule stability aids transport throughout the cell and protects against degeneration resulting from cytoskeleton breakdown. When tubulin is bound to various classes of stabilizing drugs (e.g., paclitaxel, epothilone) it assumes several characteristic overall structural conformations. Using rationale molecular design we produced several superior stabilizing-tubulin molecules (SS-tubulin) which confer greater structural stability to microtubules and thereby ameliorate the root cause of many cellular dysfunctions that arise in AD diseased cells. Gene therapy is one means to deliver our SS-tubulin; other nanotech delivery systems may work as well. We discuss the potential benefits and drawbacks of administering SS-tubulin DNA to structurally damaged regions of AD brain, particularly in conjunction with current gene therapies for AD (e.g., gene therapies that increase neurotrophins).


Scadenza validita proposta 01/11/2020      PROPONI LA TUA CANDIDATURA




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