“Immunotherapy and Gene Therapy Against Brain Amyloid”
by David Morgan, PhD
University of Florida, Tampa, Florida
Abstract:
In 1999 Shenk and colleagues demonstrated vaccination against the Aß peptide delayed plaque deposition in APP transgenic mice. Our research group began inoculating mice within 2 weeks of the publication and showed in 2000 that the vaccine also prevented memory deficits in the APP transgenic mice. Phase 2 clinical trials of the vaccine in AD patients were halted in 2002 due to autoimmune reactions, but patients with elevated antibody titers appeared to benefit. We subsequently demonstrated a monoclonal antibody against Aß could not only delay amyloid deposition but remove pre-existing deposits and restore memory function in 25 mo old APP mice. However, this clearance was associated with development of microhemorrhage secondary to increased vascular amyloid. In collaboration with a biotech partner, we demonstrated that deglycosylating the antibody and reducing its activation of microglial cells still resulted in amyloid clearance, but with minimal vascular pathology. A humanized version of this antibody is presently in clinical trials with Pfizer.
A second molecular therapeutic approach to CNS disease is gene therapy. We and others have demonstrated that localized injections of viral vectors delivering the protease neprilysin into mouse hippocampus can block amyloid formation in APP mice. However, even using several tricks to enhance distribution, only a portion of the relatively small mouse brain can be transduced. To a) access all portions of the CNS and b) concentrate therapeutic gene delivery to sites of toxicity, we used monocytes, transfected ex vivo, as carriers of therapeutic genes in APP mice. These monocytes not only enter the brain from the circulation, but they also home to the sites of CNS inflammation around the amyloid plaques and deliver a secreted form of neprilysin in sufficient quantity to arrest amyloid deposition. This approach may translate to human applications using a patient’s own monocytes to demonstrate proof of therapeutic principle for certain gene therapies without permanently modifying the patient’s genome. This demonstration would then justify transduction of stem cells or other monocyte precursors to effect more enduring benefit.
Biography:
Dave Morgan is Professor of Molecular Pharmacology and Physiology, Director of Basic Neuroscience Research for the College of Medicine and heads the Alzheimer Research Laboratory at the University of South Florida. Dr. Morgan’s research interests are aging and brain function, focusing on drugs to treat Alzheimer’s dementia. His doctoral research investigated the neurochemistry of memory and his postdoctoral studies addressed aging-related changes in rodent and human brain. Morgan became a faculty member at the University of Southern California in 1986 where his research projects focused on astrocytes and microglia in aged brain, including Alzheimer’s tissues. After moving to South Florida in 1992, Morgan participated in the development of a transgenic mouse model of Alzheimer’s disease (APP+PS1). He has developed methods to measure the damage that occurs in the brains of these mice and studied how this damage causes memory deficits in the mice. His work focuses largely on the neuro-immune interactions associated with the Alzheimer phenotype, and the role of astrocytes and microglia in the disease process. He is presently testing safer NSAID drugs, amyloid dissolving agents, amyloid immunotherapy and gene therapy to treat the Alzheimer-like changes in transgenic mouse models of the disease. This work is supported by multiple grants from the NIH, private foundations and contracts from industrial partners. An antibody against the amyloid peptide that was characterized in his laboratory has entered clinical testing in AD patients through Pfizer Inc. Morgan regularly sits on review panels for NIH and other agencies evaluating grants to develop new drugs to treat Alzheimer’s and other neurodegenerative disorders. In addition to his research activities, Morgan has consulted with both major pharmaceutical companies and small biotechnology companies regarding the development of therapeutics for Alzheimer’s disease, and advised capital investment organizations regarding the most promising therapeutic approaches to curing Alzheimer’s disease.
“Immunotherapy and Gene Therapy Against Brain Amyloid”
by David Morgan, PhD
University of Florida, Tampa, Florida
Abstract:
In 1999 Shenk and colleagues demonstrated vaccination against the Aß peptide delayed plaque deposition in APP transgenic mice. Our research group began inoculating mice within 2 weeks of the publication and showed in 2000 that the vaccine also prevented memory deficits in the APP transgenic mice. Phase 2 clinical trials of the vaccine in AD patients were halted in 2002 due to autoimmune reactions, but patients with elevated antibody titers appeared to benefit. We subsequently demonstrated a monoclonal antibody against Aß could not only delay amyloid deposition but remove pre-existing deposits and restore memory function in 25 mo old APP mice. However, this clearance was associated with development of microhemorrhage secondary to increased vascular amyloid. In collaboration with a biotech partner, we demonstrated that deglycosylating the antibody and reducing its activation of microglial cells still resulted in amyloid clearance, but with minimal vascular pathology. A humanized version of this antibody is presently in clinical trials with Pfizer.
A second molecular therapeutic approach to CNS disease is gene therapy. We and others have demonstrated that localized injections of viral vectors delivering the protease neprilysin into mouse hippocampus can block amyloid formation in APP mice. However, even using several tricks to enhance distribution, only a portion of the relatively small mouse brain can be transduced. To a) access all portions of the CNS and b) concentrate therapeutic gene delivery to sites of toxicity, we used monocytes, transfected ex vivo, as carriers of therapeutic genes in APP mice. These monocytes not only enter the brain from the circulation, but they also home to the sites of CNS inflammation around the amyloid plaques and deliver a secreted form of neprilysin in sufficient quantity to arrest amyloid deposition. This approach may translate to human applications using a patient’s own monocytes to demonstrate proof of therapeutic principle for certain gene therapies without permanently modifying the patient’s genome. This demonstration would then justify transduction of stem cells or other monocyte precursors to effect more enduring benefit.
Biography:
Dave Morgan is Professor of Molecular Pharmacology and Physiology, Director of Basic Neuroscience Research for the College of Medicine and heads the Alzheimer Research Laboratory at the University of South Florida. Dr. Morgan’s research interests are aging and brain function, focusing on drugs to treat Alzheimer’s dementia. His doctoral research investigated the neurochemistry of memory and his postdoctoral studies addressed aging-related changes in rodent and human brain. Morgan became a faculty member at the University of Southern California in 1986 where his research projects focused on astrocytes and microglia in aged brain, including Alzheimer’s tissues. After moving to South Florida in 1992, Morgan participated in the development of a transgenic mouse model of Alzheimer’s disease (APP+PS1). He has developed methods to measure the damage that occurs in the brains of these mice and studied how this damage causes memory deficits in the mice. His work focuses largely on the neuro-immune interactions associated with the Alzheimer phenotype, and the role of astrocytes and microglia in the disease process. He is presently testing safer NSAID drugs, amyloid dissolving agents, amyloid immunotherapy and gene therapy to treat the Alzheimer-like changes in transgenic mouse models of the disease. This work is supported by multiple grants from the NIH, private foundations and contracts from industrial partners. An antibody against the amyloid peptide that was characterized in his laboratory has entered clinical testing in AD patients through Pfizer Inc. Morgan regularly sits on review panels for NIH and other agencies evaluating grants to develop new drugs to treat Alzheimer’s and other neurodegenerative disorders. In addition to his research activities, Morgan has consulted with both major pharmaceutical companies and small biotechnology companies regarding the development of therapeutics for Alzheimer’s disease, and advised capital investment organizations regarding the most promising therapeutic approaches to curing Alzheimer’s disease.
