October 9, 2002
Cindy Lemere, Center for Neurologic diseases, BWH, Harvard Medical School
Since the last we met (at the Holiday Party in December), my laboratory has been growing both in terms of the number of members and the direction of our research. As you may remember, we are trying to develop a vaccine for the prevention and treatment of Alzheimer’s disease (AD), a devastating neurological disorder and the most common form of dementia in the world. We spent 2-3 years optimizing immunization protocols in regular "wildtype" mice and then applied them to several genetic mouse models of Alzheimer’s disease. Ours is the only group in the world currently working on an AD vaccine that would avoid shots and frequent doctor’s office visits by administering the vaccine via nose drops or nasal spray. We believe this method is more convenient and less costly to patients and their families.
This past year has brought many successes in the lab. We have had 10 research manuscripts accepted for publication in scientific journals or books. The lab grew from 4 to 9 people over the summer and is now holding steady at 6 researchers. Two former lab members began the first year of medical school this year. Through our experiments, we have consistently reduced the disease-like pathology in AD mouse models using our vaccine. We have found evidence to support a mechanism to explain how the vaccine works. While still somewhat controversial within the research community, this mechanism suggests that the antibodies generated by vaccination with amyloid-B peptide (AB), the neurotoxic form of the protein that gets stuck in plaques in the brains of patients with AD, shift the flow of AB protein between the brain and blood. The antibodies appear to increase the flow of AB from the brain to blood, where it is then degraded and cleared from the body. Our studies in mice have shown the potential for generating lots of antibodies using certain immune system enhancers, called adjuvants, in very small doses. The mice tolerate these treatments extremely well and appear quite healthy.
As some of you may have heard in the news, the first AD vaccine human clinical trial was initiated by Elan Corporation in the USA and Europe last fall based previous safety trials in ~100 people. In this Phase II trial, 375 patients with mild-to-moderate AD were enrolled and 300 were given injections of the AB protein plus an adjuvant to enhance antibody production. Unfortunately, by January, the trial was suspended due to "adverse events" in 4 patients. The trial was stopped completely in March. Between January and now, 17 of 300 patients have shown signs of central nervous system inflammation including headache, fever and confusion. All were treated and thankfully, most have recovered or improved significantly. The cause for these side effects is unknown but may turn out to be attributable to a hyperactive immune response to the AB peptide, itself. Humans have AB proteins already; the vaccine may have induced an autoimmune response in which the immune cells in the body start to attack its own nerve cells rather than just clearing AB from the brain. Another possibility is that the immune enhancer, the adjuvant, may have caused the side effects. Many laboratories, including our own, are working very hard to try to define the cause of these "adverse events" so as to avoid them in the future. We are currently designing new AB compounds to try to avoid the undesirable immune responses and then testing them in mouse models by specifically monitoring the changes in AB levels in brain and blood in conjunction with the reaction of immune cells in the body. We believe very strongly that there remains a very real potential for a safe and effective AD vaccine and we are working harder than ever to make it a possibility. Your contributions to our research program over the years have made a tremendous difference in what we can learn, test and accomplish. We are eternally grateful to you for your kind generosity. Thank you!