Study explores gene transfer to modify underlying course of Alzheimer’s disease

New technique that uses gene therapy delivers nerve growth factor into regions of the brain where neurons are degenerating, in order to prevent cell death and reverse cell atrophy.

Investigators at Rush University Medical Center have successfully initiated a new technique that uses gene therapy to deliver nerve growth factor into regions of the brain where neurons are degenerating, in order to prevent cell death and reverse cell atrophy, two hallmarks of Alzheimer’s disease. If successful, this could be a major step toward modifying the course of the disease. Rush is the only center in this study.

The new technique uses CERE-110 as the gene therapy agent. CERE-110 carries the Nerve Growth Factor (NGF) gene encased in a harmless viral coating, which protects the gene and facilitates its delivery to brain cells. The active part of the drug is the NGF gene, the human DNA strand that codes for the NGF protein, a natural substance that exerts positive effects on brain cells. A key objective of the study is to deliver the CERE-110 directly to the part of the brain that is almost universally affected by Alzheimer’s disease, the basal forebrain, and not to other parts of the brain where it may cause side effects.

The new drug, CERE-110, is being used by researchers at Rush as part of a Phase I study to evaluate its safety and tolerability using two different doses. Memory and cognitive function will also be assessed regularly during the two-year period of the study. Six to 12 subjects with mild to moderate Alzheimer’s disease, based on the specific cognitive tests used to classify the disease stage, will be enrolled in the study.

The first patient in the study was treated on July 27. Dr. David Bennett and Dr. Zoe Arvanitakis of the Rush Alzheimer’s Disease Center are the co-principal investigators. Bennett is director of the center. Ceregene, Inc., based in San Diego, (a minority owned subsidiary of Cell Genesys, Inc.) the developer and manufacturer of CERE-110, is funding the study.

Neurosurgery is required to precisely inject the drug into the nucleus basalis of Meynert on both sides of the brain. Dr. Roy Bakay, a Rush neurosurgeon and member of the Chicago Institute of Neurosurgery and Neuroresearch medical group, performs the surgery. Bakay is experienced in stereotactic injection and performed some of the surgeries for an earlier study at the University of California, San Diego. While neurosurgery is used to deliver NGF in both studies, the precise method of drug delivery in the Rush study has been modified in order to decrease risk and increase the potential benefit of NGF.

Results from a Phase I study by Dr. Mark Tuszynski at the University of California, San Diego, determined that there were no adverse effects from NGF detected in the subjects, an indication that the biological therapy is itself safe and well tolerated. Since the study was small and did not include placebo controls, apparent trends toward improvements in rate of cognitive decline and brain activity noted by Dr. Tuszynski must be interpreted with extreme caution. This study used genetically modified skin cells to deliver the NGF. Results from that study were presented at the American Academy of Neurology meeting in Philadelphia this past April. The study being conducted at Rush uses a more sophisticated means of delivering NGF to the brain and does not require a skin biopsy or the use of skin cells.

Alzheimer’s disease is caused by brain degeneration and is marked by the death of cells, particularly the cells (cholinergic neurons) in the basal forebrain. These cells are the primary source of the brain chemical messenger (neurotransmitter) called acetylcholine. Alzheimer’s disease impairs the production of acetylcholine, one of the main chemical messengers in the brain that is important for memory and cognitive function.

“If you can positively affect the basal forebrain, it may have a widespread effect on the entire brain because projections from that area reach out to all other parts of the brain, delivering the important neurotransmitter acetylcholine,” said Arvanitakis.

Until recently, there was no practical method to deliver NGF to the specific areas of the brain where neurons were degenerating in Alzheimer’s disease. Indiscriminate delivery of NGF to the brain would cause side effects, such as weight loss and pain.

The virus coating (AAV vector) that carries the NGF gene is well studied and has been used in several other gene transfer studies to deliver different genes to treat cancer, cystic fibrosis, and Parkinson’s disease. “Until now, it has not been used in Alzheimer’s disease,” Arvanitakis said. “The vector is no longer a true virus as it cannot replicate on its own and must be in the presence of another virus to be active. The vector will transfer the gene for NGF only to the area of the brain where it is placed. The virus is common; most people have already been exposed to it and so have developed antibodies to the virus in their blood,” she explained.

Currently, there are five Food and Drug Administration (FDA) approved medications for use in treating cognitive symptoms in patients with Alzheimer’s disease. Four try to boost the brain levels of acetylcholine by blocking the enzyme that breaks down acetylcholine. The fifth drug acts on another brain chemical. None of the available drugs are known to change the underlying neurobiology of the disease.

Extensive studies in several animal models, including primates, showed that NGF or NFG gene delivery to the basal forebrain prevented the death of the same group of cells (cholinergic neurons) which undergo severe degeneration and death in Alzheimer’s disease patients. NGF restored atrophied (shrunken) brain cells to near-normal size and quantity and also restored axons connecting the brain cells, essential for communication between cells. In humans, loss of cholinergic cells correlates with dementia severity, the density of amyloid plaques (which are abnormal protein deposits in the brains of patients with Alzheimer’s disease), and loss of synapses in the brains of Alzheimer’s disease patients.

Alzheimer’s disease is a common disease in aging, currently affecting approximately 4.5 million Americans. The number will increase as the older segment of the population increases. If there are no significant improvements in treatment, there will be a three-fold increase in the number of persons with Alzheimer’s disease in the U.S. by 2050.