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Running head: IMMUNOTHERAPY FOR ALZHEIMER'S DISEASE Immunotherapy for Alzheimer's Disease August 03, 2009 Immunotherapy for Alzheimer's Disease Introduction The ability of vaccine strategies to provide effective treatment for neurodegenerative diseases like Alzheimer's disease is still not examined appropriately. Both passive and active immunotherapy strategies have proven effective reduction of Alzheimer's Disease-like pathologies and restoration of cognitive deficits in transgenic mice. Yet, despite efficacy of the treatment, there were few concerns about a relatively small but significant occurrence of meningoencephalitis. More research is obviously required to generate an effective response against Alzheimer's disease. Alzheimer's disease leads to cognitive decline in humans. Over 12 million people are affected by this disease worldwide.
In its earlier stages the disease is characterized by cognitive decline, language deficits, progressive memory impairment, and altered behavior. Later patients with Alzheimer's disease suffer from global amnesia; their motor functions slow down, and death typically occurs within 8 - 9 years after Alzheimer's disease diagnosis. Only a relatively small percentage of patients suffering from Alzheimers disease benefit from traditional drug therapy. To a certain extent this is explained by the fact that current drug therapy is mostly focused on enhancement of existing cerebral function in patients with Alzheimers disease, while the progression of cognitive decline is not addressed.
On contrary, immunotherapy for Alzheimer's Disease is aimed to clear the neurotoxic amyloid beta peptide from the patients brain that indirectly or directly contributes to cognitive decline in such patients (Teri, Gibbons, & McCurry, 2003). Numerous trials of active immunization with the amyloid beta peptide allowed making an conclusion that immunotherapy effectively reduces cerebral amyloid plaques and leads to stabilization in cognitive function of approximately 50 % of the patients with Alzheimers disease developed good antibody responses to the amyloid beta peptide. Passive immunotherapy in animal models of Alzheimer's disease has proven its efficiency similar to active immunotherapy strategies and has proven its efficiency in approximately 50 % of patients with Alzheimers disease who did not develop an appropriate anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. However, further studies of immunotherapy for Alzheimer's disease are required to confirm observations.
The research paper provides a comprehensive review of immunotherapy for Alzheimer's disease, traces history, evolution and current status, provides insight into animal models used in preclinical research, discusses advantages and disadvantages in active and passive immunotherapy, AN- 1792 vs AAB- 001, FDA Fast Track, reviews endpoints used to measure efficacy in the AAB- 001 Elan trial and, finally, examines how has the popular press tracked this topic. Immunotherapy: History, Evolution, Current Status Immunity traces its roots back to the times, when it was found out that patients who recovered from a disease in most cases were protected from re-infection. Thucydides mentioned that during the Athens epidemic of plague that took place in 430 BC, "the same man was never attacked twice at least fatally" (Thucydides, 1934) According to Rates, children who recovered from smallpox were also never infected. It was recognized that clinical disease may convey immunity. By 18 th century, English medicine have discovered the interrelation between the fine complexion of milkmaids and their exposure to cowpox vaccine. In 1798 Edward Jenner has published scientific work according to which vaccination effectively protected people from smallpox.
Few years later numerous vaccines were developed to provide effective protection from infectious diseases (Desai & Grossberg, 2005). Most of them stimulated immune response against the viruses and infectious agents causing disease, and only few vaccines stimulated an immune response to toxins produced by these infectious agents. By the end of 19 th century von Behring and Kitasato found out that immunity to tetanus and diphtheria was conveyed by serum antibodies. The researchers discovered that antibodies from one animal could be transferred and used as a cure for another animal exposing the same symptoms of the same disease. This discovery led to the beginning of the immunotherapy era. The first successful immunotherapy application took place in 1891, when a child with diphtheria was cured.
By the beginning of 20 th century passive immunotherapy finally entered clinical practice, however, it was merely neglected when antibiotics were introduced by the end of the 20 th century. Nowadays, immunotherapy gains renewed interest as it is considered a new way to treat infectious, neurodegenerative, neoplastic and autoimmune diseases. Active and passive immunotherapy strategies became one of the most popular fields of therapeutics (Wilson, 2007). Human monoclonal or humanized antibodies enhanced the efficiency of passive immunotherapy and reduced the probability of serum sickness occurrence following the injection of xenogenesis serum to the lowest possible minimum.
Nowadays, immunotherapy gains popularity for treatment of patients with neurodegenerative diseases, such as Alzheimer's disease (Hebert, Scherr, & Beckett, 1995). Animal Models Used In Preclinical Research Although an insignificant number of species develop the behavioral, cognitive and neuro pathological symptoms of Alzheimer's disease, a number of animal models used in preclinical research have been created, ranging from huge mammals living several decades to tine vertebrates with life spans measurable in months (Woodruff-Pak, 2008). Developing an animal model allows the researchers to gain more knowledge about the pathology of Alzheimers disease and test potential efficacy of treatment. The researchers claim that as transgenic mice carry most of the abnormal genes causing problems associated with Alzheimers disease, they have been bread to manifest the symptoms and signs of Alzheimers disease, such as age-related learning and memory impairment, deposition of amyloid in the brain, loss of brain cells, etc (Morgan, Diamond, & Gottschall, 2000).
Transgenic mice are bred to carry mutant genes for amyloid precursor protein (APP), presenilin, genes producing ApoE 4, tau protein, etc (Schenk, Barbour, & Dunn, 1999). Mouse model is the most popular animal model, as it mimics the human pathology, thus allowing the researchers to test potential efficacy of treatments with greater hope of applicability to humans. Other animals are also used to study the pathology of Alzheimers disease, such as rhesus monkeys, and some others; however, they are not as popular as mice. Active Vs Passive Immunotherapy Advantages And Disadvantages Immunotherapy basically followed the development of a mouse model.
Although no comprehensive clinical study of active immunization has been presented, there are some results from subset of actively immunized patients. According to these results, all Alzheimer's disease patients with sterile encephalitis had been immunized with amyloid beta peptide; few patients had no detectable anti-amyloid beta peptide antibodies in serum; approximately 50 % of the elderly patients immunized with amyloid beta peptide generated no significant titers of anti-amyloid beta peptide antibodies; in a number of patients those who generated significant levels of serum anti-amyloid beta peptide antibodies reported little or no cognitive decline within one year after active immunotherapy (Trinh, 2003). The researchers came to conclusion that active immunotherapy with amyloid beta peptide in elderly patients is more toxic and less efficient compared to the middle-aged APP-transgenic mouse model of familial Alzheimer's disease. There is an assumption that these differences can be explained by the greater age of the patients and the reduced antibody response to vaccination, followed by drastic increase in autoimmune responses.
In vivo, passive immunotherapy of APP-transgenic mice with anti-amyloid beta peptide antibodies reversed or prevented cerebral amyloid deposition depending on whether the treatment was begun before or after cerebral amyloid deposition took place. Passive immunotherapy also has the potential to effectively reverse the pathologic accumulation of cerebral amyloid beta peptide. Yet, it is relatively difficult to conclude whether active immunotherapy is more effective than passive one, as passive immunotherapy in animal models of Alzheimer's disease provides mostly similar benefits (an evidence of effective reduction in cerebral amyloid plaques as well as stabilization in cognitive function or approximately 50 % of patients developed good antibody responses to amyloid beta peptide). Both types of immunotherapy have potential to be effective for at least 50 % of patients with Alzheimer's disease without inducing T-cell-mediated encephalitis.
Further studies of immunotherapy are required to confirm observations. AN- 1792 vs AAB- 001 (Bapineuzumab) Immunotherapy strategies for Alzheimer's disease are based on the ability of antibodies raised against A? peptides to bind to and clear A? from the brain, thus removing the peptide and inhibiting the damage to neurons that A? inflicts. (Drugs in Clinical Trials: AAB- 001) Active immunotherapy implies inoculating patients with Alzheimer's disease with peptides and inducing an individual immune response to A? within the patient. (Drugs in Clinical Trials: AAB- 001) Clinical trial of AN- 1792, that was based on the same approach was suspended due to dangerous adverse effects leading to development of encephalitis, or brain inflammation.
AN- 1972 is a synthetic form of the 42 amino acid beta amyloid peptide. It was assumed that immunization with it may reverse or prevent the development of neuro pathological hallmarks of Alzheimer's diseases, including neuritic dystrophy, including extensive amyloid plaque formation, synaptic loss and gloss (Drugs In Clinical Trials: AN 1792). In contrast to AN- 1792, AAB- 001 is a passive Alzheimer Vaccine developed by Elan Corporation and Wyeth Pharmaceuticals, which has already been granted fast-track status, in which patients are treated with humanized monoclonal antibodies with specificity to A? peptides. (Drugs in Clinical Trials: AAB- 001) AAB- 001 is a humanized monoclonal antibody that accumulates in the brain of patients with Alzheimer's disease. AAB- 001 is a genetically engineered chimeric molecule grafting an antigen recognition site derived from a mouse monoclonal antibody onto human immunoglobulin. FDA Fast Track The U.
S. Food and Drug Administration (FDA) has granted Bapineuzumab (AAB- 001) Fast Track designation for treatment of mild to moderate Alzheimer's disease. The FDA Fast Track Development Program is a designation of FDA aimed to accelerate approval of investigational new drugs undergoing clinical trials. Fast Track status is often given to medications or agents showing promise in treating life-threatening, serious medical conditions for which no other effective medication works or exists.
There were few ongoing Phase 2 studies with Bapineuzumab; the first Phase 2 trial was a randomized, placebo controlled, double-blind, multiple ascending dose study of four cohorts of about 240 patients diagnosed with mild to moderate Alzheimer's disease. The major aim of the trial was to evaluate potential safety of Bapineuzumab and the effect of treatment on functional and cognitive endpoints, biomarkers and blood serum levels. Four doses of bapineuzumab (0. 15 mg / kg , 0. 5 mg / kg , 1. 0 mg / kg and 2. 0 mg / kg ) with approximately 60 patients in each dose cohort were tested. The Alzheimer's disease patients were randomized on an 8: 7 ratio to receive bapineuzumab or placebo, resulting in approximately 32 participants receiving bapineuzumab and 28 participants receiving placebo in each dose group. (Elan and Wyeth Announce Encouraging Top-line Results from Phase 2 Clinical Trial of Bapineuzumab for Alzheimer's Disease) The researchers also examined and assessed functional and cognitive status, and each Alzheimer's disease patients participation lasted approximately 18 months. The second Phase 2 trial was an Alzheimer's beta-amyloid imaging study of 30 patients conducted in Europe. According to Elan Corporation, bapineuzumab has proven to have clinical activity for treatment of Alzheimers disease.
Although the study did not gain statistical significance on the primary efficacy endpoints, post-hoc analysis still managed to show clinically meaningful and statistically significant benefits in important subgroups of patients (Elan and Wyeth Announce Encouraging Top-line Results from Phase 2 Clinical Trial of Bapineuzumab for Alzheimer's Disease). Elan Corporation, plc and Wyeth Pharmaceuticals, a division of Wyeth initiated a Phase 3 clinical trial of Bapineuzumab (AAB- 001) Nor Apolipoprotein E 4 Carriers. Endpoints Used To Measure Efficacy In The AAB- 001 Elan Trial According to the results of the study, in non-carriers of the Apolipoprotein E 4 (ApoE 4) allele (accounting for 40 - 70 % of patients with Alzheimer's Disease), host-hoc analysis proved efficacy of bapineuzumab treatment on few key efficacy endpoints, including the Neuropsychological Test Battery (NTB), the Alzheimers Disease Assessment Scale (ADAS-cog) (assesses cognition), the Clinical Dementia Rating Sum of Boxes (CDR-SB) and the Mini Mental State Examination (MMSE). A relatively positive directional change was also observed on the Disability Assessment Scale for Dementia (DAD), however, according to the researchers, this was not statistically significant.
In addition, the preliminary evaluation of MRI results showed less loss of brain volume in patients treated with bapineuzumab compared to those receiving placebo. Smaller increases in ventricular volume were also observed in patients receiving bapineuzumab treatment versus placebo patients. As far as the progression of Alzheimer's Disease is associated with increases in ventricular volume and losses in brain volume, bapineuzumab treatment has shown clinical benefits for treatment of Alzheimer's Disease. Popular Press Coverage Immunotherapy has immediately gained national attention as a viable treatment option for Alzheimer's Disease. A large number of popular press articles is written and consistently published by science journalists to increase awareness of the problem.
As far as a significant about of public funding is used for Alzheimer's Disease research in the United States, it is very important for the U. S. citizens to understand where the funding is going as well as the benefits they receive from it. Bapineuzumab clinical trial press coverage contains mostly forward-looking statements concerning the potential of the bapineuzumab compound and reflects the nations hope to find cure for Alzheimer's Disease. Yet, some articles in popular press express concern about potential risks associated with the uncertainty of the clinical development of Bapineuzumab for Alzheimer's Disease and whether Bapineuzumab will get approval for commercialization. References Desai, A. ; Grossberg, G. (2005).
Diagnosis and treatment of Alzheimer's disease. Neurology, 64, S 34 S 39. Drugs in Clinical Trials: AAB- 001. (n. d. ). Retrieved August 3, 2009, from web Drugs In Clinical Trials: AN 1792. (n.
d. ). Retrieved August 3, 2009, from web Elan and Wyeth Announce Encouraging Top-line Results from Phase 2 Clinical Trial of Bapineuzumab for Alzheimer's Disease. (n. d. ). Retrieved August 3, 2009, from web Hebert, L. , Scherr, P. , & Beckett, L. (1995).
Age-specific incidence of Alzheimer's disease in a community population. JAMA, 273: 1354. Morgan, D. , Diamond, D. , & Gottschall, P. (2000). A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature, 408: 982. Schenk, D. , Barbour, R. , & Dunn, W. (1999).
Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400: 173. Teri, L. , Gibbons, L. , & McCurry, S. (2003). Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA, 290: 2015. Thucydides. (1934).
The Peloponnesian War. New York: Modern Library. Trinh, N. (2003). Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: A meta-analysis. JAMA, 289 (2), 210216. Wilson, R. (2007).
Relation of cognitive activity to risk of developing Alzheimer disease. Neurology, 69 (20), 19111920. Woodruff-Pak, D. S. (2008).
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