Progress Against Alzheimer's Disease: New Research on Possible Vaccine
by Kenneth J. Bender, Pharm.D., M.A.| Geriatric Times |  |
September/October 2000 | |
Vol. I | |
Issue 3 |
A vaccine that may prevent the development and reverse the buildup of ß-amyloid plaques in the human brain was highlighted in a plenary session of the World Alzheimer Congress 2000, held July 9-18 in Washington, D.C. The initial results of a Phase I clinical trial against this marker for Alzheimer's disease (AD) were presented at the meeting.
The apparent safety of the vaccine, reported by Dale B. Schenk, Ph.D., vice president of discovery research at Elan Pharmaceuticals, was enthusiastically received by both the media and congress attendees. This first human study of the vaccine had been widely anticipated since last year's finding that-injected peripherally into transgenic (TG) mice bred to develop the amyloid plaques-the vaccine appeared to prevent plaque deposition in the brains of the youngest animals. The vaccine also appeared to markedly reduce the extent and progression of the plaques and associated neuropathology in older specimens (Schenk et al., 1999).
New Research Gives Hope
Bill Thies, Ph.D., the Alzheimer's Association's vice president of medical and scientific affairs, remarked to the press, "Just a few years ago, talk of a potential vaccine for Alzheimer's disease would have been viewed with much skepticism and disbelief. Announcements like this, that are grounded in solid scientific research, give us tremendous hope."
The vaccine comprises a synthetic ß-amyloid peptide (Aß42), the 42-amino acid, principal form of the peptide within amyloid plaques, along with an adjuvant to prompt antibody production. The TG mice in the Schenk et al. 1999 study that received the vaccine were genetically altered to overproduce amyloid precursor protein (APP), leading to excessive deposition of ß-amyloid peptide and plaque formation.
"Amyloid plaques act as a brain invader," Schenk explained to the press. "We are optimistic that we can attack this invader at its source and eventually help the millions of people with families worldwide who are living with this devastating disease."
The progress apparent in the vaccine research moving from animal model to a Phase I human safety trial was supported by the results of additional work with TG mice that were reported separately at the congress. These results indicated the vaccine improved cognitive functioning in behavioral tests. This study by Christopher Janus, Ph.D., and colleagues at the University of Ontario, evidenced an improved performance of immunized TG mice in the water maze paradigm, in comparison to TG mice receiving a similar but nonactive vaccination (Janus et al., 2000).
Janus and colleagues had previously found that these animals developed ß-amyloid plaques by three months of age, and they demonstrated cognitive impairment in spatial learning and spatial memory, relative to non-TG mice. In their present investigation, monthly immunization of the mice began at six weeks of age with a booster at eight weeks. The mice then underwent monthly behavioral testing at 10 weeks. Janus et al. reported observing better cognitive functioning in the active-immunized animals than controls at the first behavioral test at 10 weeks.
"These findings suggest that, unexpectedly, immunization with Aß42…may improve performance in the water maze, and that this improvement can occur at a time prior to notable deposition of ß-amyloid plaques in the hippocampus," they indicated.
While such evidence of beneficial effect on function as well as pathology is encouraging, Schenk cautioned against yet assuming that it is a harbinger of clinical improvement in patients with AD. "Of course, mice aren't humans," he remarked to an Associated Press reporter.
Schenk told the plenary session that a single injection, with different amounts of the investigational vaccine referred to as AN-1792, was well-tolerated over a six-week monitoring period by 24 patients with early-onset AD at several U.S. sites (Schenk et al., 2000b). The complete Phase I series will involve approximately 100 patients in the United States and the United Kingdom, and it will include multiple doses over a longer time period to more closely resemble a therapeutic regimen.
"We are extremely pleased with the progress of our Phase I trials, which have shown that AN-1792 is well tolerated by the patients," Schenk commented to the press. He added, "During the course of our research, we also developed a greater understanding of how the vaccine works to clear amyloid plaques out of the brain and prevent additional plaques from forming."
Targeting ß-Amyloid
Therapeutic strategies targeting the ß-amyloid plaque are based on the hypothesis that the lesion is not just a marker of the illness, but is integral to its pathogenesis. This hypothesis has its detractors, and there are others offering alternatives such as a malfunctioning tau molecule, integral to nerve cell structure and implicated in neuronal tangles. The imminent clinical testing of an agent that prevents and/or reduces ß-amyloid plaques, however, could finalize the debate over the pathogenic role of the lesion.
Deploying investigational agents against ß-amyloid has been facilitated by the development of TG mice with these lesions. In-vitro methods are also utilized to analyze the effect of the agents on the plaques in tissue samples, and at molecular level sites of the ß-amyloid peptide and peptide fibrils within the plaque.
One approach against ß-amyloid under investigation by several laboratories is applying secretase inhibitor compounds. This uses the recently gained expertise in developing protease inhibitors for AIDS; these block formation of the ß-amyloid peptide. Others are developing compounds that may inhibit aggregation of the peptide into plaques. Genome breakthroughs may enable preventing an antecedent of excessive production or aggregation of the ß-amyloid peptide; or they may counter the possible detrimental effect of the lipoprotein APO E4, or other factors, on its dispersal.
In another presentation at the congress, Beka Solomon, Ph.D., of Tel Aviv University, described her success in stimulating production in guinea pigs of antibodies that lock specifically on the epitope site EFRH (indicating only the four amino acids: glutamic acid, phenylalanine, arginine and histidine) sequenced 3-6 within the human ß-amyloid peptide. Her group had previously determined this to be integral to arresting and reversing its aggregation (Solomon et al., 1996, 1997).
In contrast to injecting animals with Aß42 and an adjuvant, Solomon's group administered intranasally filamentous phages, a single DNA strand, displaying EFRH peptide (Solomon and Frenkel, 2000). The immunoresponse to the phage body obviated the need for an adjuvant and occurred more rapidly than to the ß-peptide injected with adjuvant, according to the presenters. It is not known, however, whether intranasal phage immunization would be clinically applicable or the immune reaction tolerable.
Acknowledging that immunization seems an unlikely method of attacking existing plaques in the brain, Schenk and colleagues have explained how the resultant antibodies can overcome the blood-brain barrier to transfer from serum to cerebrospinal fluid at several sites, including the circumventricular organs, pial surfaces and the Virchow Robin spaces (Schenk et al., 2000a). While antibody titer is initially low relative to serum, Schenk et al. (2000a) noted that once an antibody has bound to ß-amyloid peptide within a plaque, it is unlikely to exit the brain before locking on to another. "Over periods of months, such flux may be sufficient to alter the delicate equilibrium of ß-peptide deposition," they suggested.
With their most recent findings published in the Aug. 1 issue of Nature Medicine, Schenk's group demonstrated that the mechanism of immune response to the ß-amyloid peptide within the plaque is mediated through the humoral system rather than cellularly (Bard et al., 2000). Introduction of the specific antibodies alone resulted in the same action on the ß-amyloid as generating antibody and T-cell response to the vaccine. This discovery opens the possibility that, if the antibodies from vaccination prove therapeutic, the preparation and administration of human monoclonal antibodies could prompt a more immediate effect, and serve patients with inadequate immunoresponse to the vaccine.
The researchers were able to further characterize the mechanism of antibody disruption of the amyloid plaque as Fc-mediated phagocytosis. Monocytes or microglia in the brain were attracted to the "flag" Fc terminal portion of the antibody that attached to the peptide in the plaque, and they subsequently engulfed and destroyed the antibody-amyloid peptide complex. Comparison of cultures with plaque tissue and these scavenger cells, with and without the antibodies, elegantly confirmed this mechanism of amyloid plaque dissolution.
"The mechanism of action is true clearance of existing plaque," Schenk told Geriatric Times. "The amyloid hypothesis states that Aß [ß-amyloid] is the cause of Alzheimer's disease. If this proves to be true, then this [vaccine] should alleviate all the symptoms, or at least block progression of the disease as we know it."
With research on neurotropics and nerve regeneration also growing apace and promising increased capacity to repair neuronal damage, prospects for arresting and remediating Alzheimer's disease have never been brighter.
References
Bard F, Cannon C, Barbour R et al. (2000), Peripherally administered antibodies against amyloid ß-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Medicine 6(8):916-919.
Janus CG, Pearson JD, Chishti AM et al. (2000), Changes in cognitive characteristics of TG APPCRND8 mice at early stages of immunization with beta amyloid peptide. Presented at the World Alzheimer Congress 2000. Washington, D.C.; July 9.
Schenk D, Barbour R, Dunn W et al. (1999), Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740):173-177 [see comment].
Schenk DB, Seubert P, Lieberburg I, Wallace J (2000a), ß-peptide immunization. A possible new treatment for Alzheimer disease. Arch Neurol 57(7):934-936.
Schenk DB, Bard F, Barbour R et al. (2000b), A possible vaccine for treatment of Alzheimer's disease. Presented at the World Alzheimer Congress 2000. Washington, D.C.; July 11.
Solomon B, Frenkel D (2000), Generation of autoantibodies towards Alzheimer's disease vaccination. Presented at the World Alzheimer Congress 2000. Washington, D.C.; July 12.
Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997), Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A 94(8):4109-4112.
Solomon B, Koppel R, Hanan E, Katzav T (1996), Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A 93(1):452-455.