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Understanding Alzheimer's disease and brain


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  • 1. Newer drugs in pipeline for Alzheimer's
  • 2. Goal of Clinical Research are to SLOW or STOP disease progression and PREVENT Alzheimer's disease. So early diagnosis is essential and various initiatives are underway to identify at risk individual, enable early diagnosis and track treatment.
  • 3. Genetics of Alzheimer's Disease AD has two types, Early onset and Late onset, and both have genetic links. 1. Early-Onset AD Early-onset AD is a rare form of AD, affecting only about 5 percent of all people who have AD. It develops in people ages 30 to 60. Some cases of early-onset AD, called familial AD (FAD), are inherited. FAD is caused by a number of different gene mutations on chromosomes 21, 14, and 1, and each of these muta-tions forms abnormal proteins. Chromosome21 causes abnormal amyloid precursor protein (APP). Chromosome 14 causes abnormal presenilin 1. Chromosome 1 leads to abnormal presenilin 2.
  • 4. 2. Late-Onset AD Most cases of Alzheimer¶s are of the late-onset form, developing after age 60. One predisposing genetic risk factor is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions needed to make a protein that helps carry cholesterol in the bloodstream. APOE comes in several different forms, or alleles. Three forms²APOE e2, APOE e3, and APOE occur. At present, APOE testing is used in a research setting to identify study participants who may have an increased risk of developing AD.
  • 5. SORL1 14 January 2007 online ed. of Nature Genetics, study implicates gene SORL1 in late-onset Alzheimer¶s Disease. SORL1²Sortilin-related, low-density lipoprotein receptor class A repeat-containing protein. 0 Gene involved in cellular sorting process for APP Researchers found that when SORL1 is present at low levels or in a variant form, beta-amyloid levels increase and may harm neurons Association with AD has been identified and confirmed in three separate studies
  • 6. Alzheimer's disease and brain Plaques and tangles are the hallmark of Alzheimer's Disease People with AD have lots of two abnormal structures: -: beta-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells -: neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell Tangle Plaque
  • 7. Beta-amyloid Plaques Amyloid precursor protein (APP) is the precursor to amyloid plaque. 1. APP sticks through the neuron membrane. 2. Enzymes like alpha-secretase, beta-secretase, and gamma- secretase cleave APP into fragments of protein, including beta- amyloid (38 to 42). 3. Beta-amyloid fragments esp 42 are more vulnerable to form insoluble plaques after inflammatory and oxidative stress. 4. These clumps disrupt the function of neurons ( connection of neurons and cause death of neurons ) 1 2 3
  • 8. Neurons are internally supported by microtubules and TAU protein help in stabilizing microtubules. In Alzheimers TAU is hyperphosphorylated and this leads to clumping of neurons.
  • 9. Changes in brain Amyloid plaques Tau tangles Other abnormal protein deposits Reduced oxygen flow to tissues Toxic processes
  • 10. Four main strategies in anti- amyloid therapy 1. Immunotherapy ( active and passive ) to modify the process by which Amyloid beta is converted to senile plaque. 2. Secretase inhibitors 3. Selectively reduce beta amyloid 42, by shifting production to less toxic 38 and 40.(tarenflurbil) 4. Inhibit aggregation of Amyloid beta, inhibiting plaque formation. (tramiprosate- GAG)
  • 11. The advances in our knowledge about the mechanisms and risk factors associated with AD have expanded the types of interventions under study. These trials are examining a host of possible interventions, including cardiovascular treatments, hormones, type 2 diabetes treatments, antioxidants, omega-3 fatty acids, immunization, cognitive training, and exercise, among others.
  • 12. Summary about the our present understanding of Alzheimer's Previous works have shown a number of attributes shared by both familial and sporadic AD. Mutations in the genes for b APP, presenilin-1 or -2, account for nearly all of the early-onset familial cases of AD. Most late-onset AD is sporadic yet subject to genetic influences, including the e 4 allele of apolipoprotein E and a haplotype of polymorphisms in proinflammatory cytokine loci. Therefore, the ongoing development or pathogenesis of the disease is clearly a complex pathway involving numbers of complex mechanisms, most likely both genetic and physiological. New pathogenic mechanisms continue to be suggested by various methodologies. Most hypotheses include an overproduction or accumulation of the 42-amino acid form of the amyloid b -peptide, produced from b APP by the b - and g -secretases. However, there is also evidence for aberrant phosphorylation, non-enzymatic glycosylation, oxidation, nitrosylation, and other posttranslational modifications of multiple proteins. Thus, critical insights might be gleaned from additional understanding of protein levels and alterations.
  • 13. Phase 1 trials: Small studies in healthy volunteers or patients that identify drug effects, measure side effects of different doses, and explore efficacy.( finding safe dose) Phase 2 trials: Larger studies in patients that evaluate efficacy and assess side effects.(screen to determine the activity against disorder)
  • 14. Phase 3 trials: Larger studies that build on earlier results and determine efficacy and safety; results form basis for FDA approval. Phase 4 trials: Post- approval studies that provide more information on risks, benefits, and optimal use.
  • 15. Phase III interventional trials Phase III clinical studies provide the chief evidence for safety and effectiveness that the U.S. Food and Drug Administration (FDA) considers in deciding whether to approve a drug. The following Alzheimer drugs in Phase III clinical studies are ³interventional drugs´ designed to slow or stop the progression of the disease
  • 16. Dimebon, a drug used in Russia for its antihistaminic effect for over 2 decades, is also a ChEI and N-methyl-D-aspartate (NMDA) inhibitor, the 2 mechanisms of action of existing AD drugs. However, it is now believed that dimebon¶s primary mechanism of action in AD is stabilization of mitochondrial function. Dimebon is now in Phase III of clinical development. Phase II study in patients with mild to moderate AD, in which dimebon 20 mg TID was associated with significant benefit compared with placebo. The main tolerability finding was a higher rate of incident depression in the dimebon group compared with the placebo group.
  • 17. Immunotherapy 1. Anti Amyloid immunotherapy (Passive) Bapineuzumab Amyloid plaques, another of the pathologic hallmarks of AD, are abnormal, insoluble, extracellular aggregates of Aȕ peptide. Immunotherapy employing monoclonal antibodies to Aȕ is designed to bind to and remove the beta-amyloid peptide that accumulates in the brains of individuals with Alzheimer's. Bapineuzumab is given as a series of injections, delivering antibodies to beta-amyloid. This approach is called ³passive immunization,´ since the body is receiving the antibodies via the drug, rather than generating the antibodies itself. This drug is being tested in individuals with mild to moderate Alzheimer's. Of these, the only one to have reached Phase III trials is bapineuzumab, the subject of the largest clinical trial program to be undertaken for the treatment of AD. Neurotoxicity which is a potential serious adverse effect associated with previous anti-amyloid immunotherapies is addressed in this trials
  • 18. Solanezumab is another monoclonal antibody against Aȕ peptide that has completed 1 Phase II trial Phase III trials were initiated in May 2009 to evaluate the safety and efficacy of LY2062430 400 mg IV administered every 4 weeks for 80 weeks.
  • 19. 2. Active immunisation Based on the amyloid cascade hypothesis, the therapeutic strategy of active immunization targeting Aȕ has generated widespread interest. The first-generation Aȕ vaccine, AN1792, underwent a large Phase I trial, but during Phase II there was 6% incidence of aseptic meningoencephalitis led to discontinuation of the AN1792 development program, many active immunization strategies are now being pursued in Phase I and II trials like ACC-001 and CAD106. These vaccines are given and antibody response are evaluated along with cognitive response.
  • 20. Targetting Tau Aggregated Tau correlates closely with demetia symptoms. Rember is a Tau- aggregation inhibitor. Phase II trial on patients with mild to moderate Alzheimer's disease showed 81% reduction in rate of cognitive decline after 50 weeks of rember 60mg. Davunetide intranasal is another Tau-based drug in phase II trial showing improvement with memory tests.
  • 21. TRx0014 (Methylthioninium Chloride) TRx0014 is a proprietary formulation of an old and well-known drug, methylthioninium chloride (MTC), or methylene blue, a deep-blue dye used as a tissue stain in biology, as well as in analytical chemistry and numerous industrial products (eg, ink). Its investigation as a potential treatment for AD was based on its reported ability to interfere with tau aggregation by acting on self-aggregating truncated tau fragments. Phase II trial of TRx0014 was success and phase III is expected to start soon.
  • 22. LY450139 The neurotoxic Aȕ peptide is generated by cleavage of APP by ȕ- and Ȗ-secretases. Inhibitors of Ȗ-secretase thus present an attractive option for AD therapy. BMS-29989767 and LY411,57568 lowered levels of Aȕ in the brain in animal studies of Ȗ-secretase inhibitors. LY450139 is the first selective Ȗ-secretase inhibitor for the treatment of AD to reach Phase III testing
  • 23. Rosiglitazone Insulin, insulin receptors, and insulin-sensitive glucose transporters are abundant in the medial temporal regions of the brain that support the formation of episodic memory. Insulin signaling is now known to play a role in memory functions and may also play a part in the regulation of APP and Aȕ. In addition, Aȕ accumulation in the brains of patients with AD may be the result of impaired clearance of Aȕ by Aȕ-degrading enzymes, including insulin degrading enzyme. These findings suggest that insulin-related CNS abnormalities may cause or exacerbate cognitive impairment, and that treatment of insulin resistance may reduce the risk of AD or delay its development. Rosiglitazone, a peroxisome proliferator±activated receptor-Ȗ agonist originally developed and marketed for the management of diabetes, is the leading drug in clinical development for AD based on the insulin resistance hypothesis.
  • 24. Huperzine A Huperzine A, derived from the Chinese herb Huperzia serrata, was identified by Chinese scientists in the 1980s as a potent, reversible, and selective acetylcholinesterase inhibitor. More recently, a variety of potential neuroprotective effects have been reported that may be of benefit in the treatment of AD. In a Phase II study conducted in the United States and completed in November 2007, 210 patients with mild to moderate AD received huperzine A 400 ȝg PO BID for 16 weeks showed cognitive improvement. Phase III trial anticipated.
  • 25. Ampakines CX717 belongs to a therapeutic class known as ampakines, which are positive allosteric modulators of AMPA (Į-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)±type glutamate receptors. Ampakines have been found to reduce age-associated memory deficits in animal models. Two different doses of CX717 are being tested in a Phase II pilot study in patients with mild to moderate AD.
  • 26. ELND005 (scilloinositol) ELND005 (formerly AZD 103) is a cyclohexanehexol stereoisomer, scillo-inositol. Inositol has 8 possible stereoisomeric forms, of which 3 are found in the human brain. Among these, the most common form is myoinositol, which is available as a nutraceutical. Only scilloinositol has been found to reduce the accumulation of soluble Aȕ oligomers and reverse memory deficits in the brain of transgenic mice. Phase II trial of the safety and efficacy of 3 doses of ELND005 is underway.
  • 27. Intranasal Insulin Reduced brain insulin signaling and low CSF-toplasma insulin ratios have been observed in patients with AD.72 After intranasal administration, insulinlike peptides follow extracellular pathways to the brain within 15 minutes. Insulin significantly improved scores on measures of working memory , attention, and functional status. Insulin was also associated with a significant increase in the Aȕ 40/42 ratio. Phase II trials of intranasal insulin aspart are currently in progress
  • 28. Lithium Glycogen synthase kinase±3 (GSK-3) activity has been associated with AD because of its role in the phosphorylation of tau and regulation of the production of Aȕ.120,121 Lithium has been found to inhibit GSK-3 activity122 and to provide a significant and dosedependent reduction in the expression of GSK-3b, butnot GSK-3a, that was specific to hippocampal cells. Despite this suggestive basic science, no further clinical development of lithium has been pursued since the 2005 completion of a small Phase II trial. Ongoing concerns about the safety, tolerability, and monitoring requirements associated with clinical use of lithium constitute a serious impediment to its further development for the prevention of AD.
  • 29. MK-0952( Phosphodiesterases) Phosphodiesterases (PDEs) are an important family of proteins that regulate intracellular levels of cyclic adenosine monophosphate. Compounds that inhibit PDE4 are neuroprotective, neuroregenerative, and antiinflammatory, and preclinical studies have indicated that PDE4 inhibitors may counteract deficits in longterm memory caused by overexpression of mutant forms of human APP. A Phase II trial of the PDE4 inhibitor was completed in late 2007, results yet to publish.
  • 30. PBT2 PBT2 is a metal protein±attenuating compound that affects the Cu2(+)- and Zn2(+)-mediated toxic oligomerization of Aȕ seen in AD. As such, it is considered an antifibrillar agent with a unique mechanism of action.
  • 31. PF-04494700 (RAGE) The receptor for advanced glycation end products (RAGE) has been found to bind to Aȕ and mediate its transport across the blood±brain barrier.134 A series of elegant experiments in mouse brain slices of entorhinal cortex (the first area of the brain to exhibit damage in AD) indicated that the RAGE±Aȕ complex suppresses long-term potentiation, at least in part via activation of p38 mitogen-activated protein kinase.Thus suggested that an inhibitor of RAGE might have therapeutic benefit in AD. A large Phase II safety and efficacy trial is now underway.
  • 32. PRX-03140 PRX-03140 is a highly selective, small-molecule agonist of 5-HT4, a specific G-protein±coupled receptor. In preclinical studies, PRX-03140 was found to improve cognitive function by increasing levels of acetylcholine, soluble APP, and brain-derived neurotrophic factor in regions of the brain known to be important for memory. PRX-03140 has entered Phase IIb development
  • 33. Raloxifene Raloxifene, a selective estrogen-receptor modulator, is approved for the treatment and prevention of osteoporosis in postmenopausal women. After 3 years of treatment, the 120-mg dose, but not the 60-mg dose, was associated with a reduction in risk for MCI (RR = 0.67) or AD (RR = 0.52). This finding, supported by evidence suggesting that estrogen may have a protective effect against Dementia, led to the clinical development of raloxifene for the treatment of AD. Phase II trial underway.
  • 34. RO5313534 RO5313534 is a partial nicotinic Į7±receptor agonist. Three doses of RO5313534 were evaluated in a Phase IIa trial in 80 patients with mild to moderate AD. SB742457 SB742457, a small-molecule antagonist of 5-HT6, is in the second round of Phase II testing. In preclinical studies, antagonists of 5-HT6 were found to variably enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission; in human studies, they were associated with benefit in terms of several tests of learning and memory.
  • 35. SK-PC-B70M SK-PC-B70M is composed of the oleanolic glycoside saponin±enriched fraction of Pulsatilla koreana (Korean pasque flower), which has been found to have neuroprotective and cognition-enhancing effects in animal models. A Phase II study in patients with mild to moderate AD was completed in January 2009.
  • 36. Omega-3 Fatty Acids Docosahexaenoic acid- omega-3 Fatty acid found in fish oil slower the rate of cognitive decline in patients who did not carry the apolipoprotein E 4 gene.
  • 37. From all these one thing seems clear: if disease modifying drugs are to be effective in slowing or stopping Alzheimer's disease, they should be administered early in the course of the disease, ideally before symptoms become apparent. Thus reinforcing the need to identify high- risk individuals as early as possible. There is a great deal of hope that with early diagnosis and effective treatment, Alzheimer's disease will become a preventable and treatable disease.