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Emerging Therapies for Alzheimer’s Disease
platform in a pool of water.
Phase II studies demonstrated significant immunity against amyloid plaques. Along these lines, the monoclonal anti-Aβ
effects on Alzheimer’s Disease Assessment Scale–Cognitive Subscale antibody bapineuzumab is currently the subject of phase III trials.
performance and global function, as tested by the Clinical Dementia Rating to AN-1792, bapineuzumab is a humanized antibody that does not require the
Scale Sum of Boxes test.
However, phase III trials of tarenflurbil recently body to mount an immunological response to target Aβ. It is hoped that by
failed to show efficacy. Body fluid analyses are ongoing in order to using a passive approach, the adverse effects seen in the AN-1792 trial will be
determine whether the desired Aβ
-lowering effect was actually achieved. circumvented while simultaneously retaining the benefits. In addition, two
Many other compounds that modulate γ-secretase activity are currently other monoclonal antibodies, LY2062430 (Lilly) and RN1219 (Pfizer), are
under study, including non-steroidal anti-inflammatory drugs, which act on currently the subject of clinical trials.
γ-secretase to reduce Aβ
and increase the shorter, less amyloidogenic 38-
amino acid peptide.
Another interesting line of recent research involves the role of oxidative stress
Aggregation and mitochondrial dysfunction in the pathogenesis of AD. Several studies
Many researchers believe that soluble Aβ
molecules do not become have implicated oxidative stress in the exacerbation of plaque formation and
particularly toxic until they aggregate into fibrils and plaques.
This has led to the alteration of APP and Aβ metabolism.
It has also been shown that Aβ
therapies targeting the aggregation of Aβ
. Tramiprosate (Alzhemed, exerts toxic effects on mitochondria, perhaps by altering mitochondrial
Neurochem), an Aβ
aggregation inhibitor, has been well studied and permeability.
Along these lines, dimebon (Medivation), a drug believed to
showed initial promise.
Unfortunately, the study was ultimately halted due inhibit mitochondrial permeability, as well as being a weak cholinesterase
to the failure of large phase III trials.
However, Elan Pharmaceuticals is inhibitor and N-methyl-D-aspartate-receptor antagonist, has recently
currently studying a molecule known as ELND005 in a phase II safety and demonstrated encouraging results in phase II study. This randomized,
efficacy study. ELND005 is a scyllo-inositol molecule that acts as an Aβ placebo-controlled trial showed significant improvement over placebo on
aggregation inhibitor that may help to prevent or inhibit the build-up of measures of cognition, activities of daily living, and global function.
amyloid plaques in the brain. Studies of the drug using mouse models of AD effect was seen at six months, and an additional 26-week extension of the
found that the drug modified the disease process when used as a study showed maintenance of the benefits from dimebon. The drug was well
prophylactic or therapeutic.
In addition, phase I studies found this drug to tolerated and is now the subject of phase III trials.
be well tolerated, orally bioavailable, and with CSF concentrations in humans
that had been effective in mouse models of AD. Several other aggregation Although all of the potential therapies discussed above hold promise, many
inhibitors are in pre-clinical and clinical development. researchers hold out even greater hope for treatments that may ultimately effect
neural regeneration itself. Although the concept of neurogenesis in the adult
Increasing Clearance of Aβ
brain is a new one,
it presents researchers with perhaps the most tantalizing
A potential ‘Alzheimer’s vaccine’ has long been an interest for researchers and mode of treating patients with AD, apart from completely preventing the
a hope for patients and families. The idea of using the body’s own immunity disease. If the process of neurogenesis could be better understood, perhaps
to combat amyloid plaques has great appeal, but the most promising researchers could learn to promote the formation of new neurons in the
candidate of this approach to modifying AD ran into serious problems. The diseased portions of the brains of those with AD.
Tuszynski et al. tried just such
drug in question, AN-1792, was designed to present the body with Aβproteins an approach when they implanted genetically modified nerve-growth-factor-
in order to induce active immunity against Aβ
and amyloid plaques. Studies secreting cells into the nucleus basalis of eight patients with early-stage AD.
of AN-1792 in mouse models of AD appeared positive, with evidence that This approach appeared safe and tolerable in these patients. This is clearly an
plaques were both prevented and reduced.
Unfortunately, when trials began area of development that will require many more years of study, and many
in elderly human subjects with AD, approximately 6% of patients developed molecules purported to stimulate neurogenesis are currently being studied.
aseptic meningoencephalitis, necessitating the termination of the study.
Interestingly, subsequent analysis of the data showed that subjects who Although slow in arriving, many of the approaches described above, whether
developed high titers of antibodies to Aβ
seemed to decline more slowly, and inhibiting Aβ production, modifying secretase activity, reducing Aβ
autopsy reports indicated that despite diagnostic neuropathological features of aggregation, or increasing clearance of Aβ, hold promise for actual
AD, these patients also had regions in the brain where amyloid appeared fully modification of the AD process itself, rather than simply managing symptoms.
As a result of the serious adverse events seen in the AN-1792 study, Hopefully, these emerging treatments will provide patients and families with
many researchers have turned to immunotherapies that rely on passive new, more effective ways of combating AD in the very near future. ■
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