Results look promising in Alzheimer’s gene therapy trial

Surgical placement of genetically modified tissue directly into the brains of patients with Alzheimer’s disease, an experimental approach to delaying brain cell loss associated with the disease, leads to increased metabolic activity in the brain, with cells apparently responding to the insertion of growth factor-producing grafts, according to preliminary findings reported April 27 at the American Academy of Neurology meeting in San Francisco.

Though the Phase I study conducted at the University of California, San Diego (UCSD) was small and designed to test safety and toxicity, the subjects may also show some early indications of reduction in the advancement of their disease, according to the study’s principal investigator Mark Tuszynski, M.D., Ph.D., professor of neurosciences at the UCSD School of Medicine.

"These results are intriguing," said Tuszynski.  "If these effects are borne out in larger, controlled trials, this could be a significant advance over existing therapies for Alzheimer's disease."

Eight volunteers diagnosed with early-stage Alzheimer’s disease participated in this study, with the first surgery performed in April 2001 at UCSD’s John M. and Sally B. Thornton Hospital. Patients’ own skin cells were genetically modified in culture to produce Nerve Growth Factor (NGF), a naturally occurring protein that prevents cell death and stimulates cell function. The NGF-producing cells were then surgically implanted into a deep brain region where cholinergic cell degeneration occurs in Alzheimer’s disease. The cholinergic system is important in memory and cognitive function. Patients received the implanted grafts in targeted areas on either the left, right or both sides of the brain.

This human trial was undertaken following extensive studies in primates conducted by Tuszynski and colleagues , which showed that grafting NGF-producing tissue into the brains of aged monkeys restored atrophied brain cells to near-normal size and quantity, and also restored axons connecting the brain cells, essential for communication between cells.

With the last human subject now more than a year beyond surgery, no adverse effects from the NGF-producing implants have been detected in the subjects, an indication that the biological therapy is itself safe and well-tolerated.

The procedure initially was performed while patients were awake but lightly sedated. Two patients moved as the cells were being injected, resulting in bleeding in the brain. One of these patients died of acute myocardial infarction (heart attack) five weeks later. Following these events, the protocol was redesigned with patients given general anesthesia during the procedure, and subsequent procedures were performed without complication.

The small-scale study did not include placebo controls, and doctors and patients knew that the procedure was performed (they were not “blinded”). Because of this, Tuszynski is cautious about preliminary findings regarding the cognitive function of the subjects. However, all of the subjects underwent standard cognitive testing before and following surgery, and reductions in rates of cognitive decline compared to their pre-operative function were noted. The six subjects who successfully completed the surgery showed a 50 percent reduction in their annual rate of decline on one of the measured cognitive scales. On another scale, the subjects showed a reduced rate of decline that persisted over the 1.5- to two-year period of the study.

Positron Emission Tomography (PET) imaging of the patients showed increased metabolic activity in the areas of the brains of patients after treatment with NGF, compared with non-treated Alzheimer’s disease patients. An autopsy of the patient who died showed active NGF production in the brain, and a growth response of brain cells to the NGF delivery.

Based on these results, Tuszynski concludes that the NGF implants are safe and well-tolerated by patients, and when performed with patients fully anesthetized, the injection procedure is safe.

Tuszynski is also director of the Center for Neural Repair at UCSD and a neurologist with the UCSD Alzheimer’s Disease Research Center (ADRC) and San Diego Veterans Affairs Medical Center.

Co-authors of the AAN abstract, in addition to Tuszynski, are Leon Thal, M.D., UCSD chair of neurosciences and director of the UCSD ADRC; Mary Margaret Pay, R.N. of the UCSD ADRC; Hoi-Sang U, UCSD professor of surgery; Roy Bakay, M.D., neurosurgeon at Rush University Medical Center in Chicago; John Alksne, M.D. UCSD professor of surgery; David Salmon, Ph.D., UCSD professor of neurosciences and member of the ADRC; Gilbert Ho, M.D., Assistant Professor of Neurosciences at UCSD: G. Tong, M.D., Ph.D., Assistant Professor of Neurosciences at UCSD; Armin Blesch, Ph.D., Assistant Professor of Neurosciences at UCSD; Lee Vahlsing , M.S., specialist at UCSD; James Connor, Ph.D., Project Scientist at UCSD; S. Potkin, M.D., Professor of Neurology at UC Irvine; and Christine Gall, M.D., Professor of Neurobiology at UC Irvine.

This work was supported by the Shiley Family Foundation and The Institute for the Study of Aging in New York.

A new Phase I/II study, using direct NGF gene delivery to the brain thereby eliminating the need for grafting cells, will be led by David Bennett, M.D., neurologist and director of the Rush University Alzheimer’s Disease Center, and Zoe Arvanitakis, M.D., neurologist at Rush University Medical Center in Chicago. Additional sites will be enrolled as subsequent phases of the trial proceed, sponsored by Ceregene, Inc., a San Diego-based biotechnology company. Dr. Roy Bakay, a Rush University Medical Center neurosurgeon, will perform the surgery.  Bakay, an experienced neurosurgeon in performing stereotactic injection, participated in some of the UCSD surgeries.

The University of California holds the patent to this technology. The exclusive world-wide licensee is Ceregene, Inc. a biotechnology company focused on the development and commercialization of gene therapies for neurological disorders including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Ceregene was launched in January 2001 and is a majority-owned subsidiary of Cell Genesys, Inc. (Nasdaq: CEGE), which is headquartered in South San Francisco, CA. The University of California and some of its investigators have a financial interest in Ceregene.

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