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Alzheimer's Research

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Title: Alzheimer's Research


1
Alzheimer's Research
  • Yesterdays Discoveries
  • Todays Work
  • Tomorrows Promise

2
Knowledge and ignorance
  • We don't know one-millionth of one percent about
    anything. - Thomas Edison
  • "If artists and scientists share passion as a
    driving force, they also share the same energy
    emotion, a sense of wonder at the universe, this
    endless source of question marks."
  • He who knows little, quickly tells it.

3
Outline
  • 1. How we learned what we know- The discoveries
    of yesterday
  • 2. Our current state of knowledge, and the
    treatments available-the work of today
  • 3. The drugs in testing for tomorrow, and what we
    can look forward to-The promise of the future

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Alois Alzheimer and Frau Auguste D
  • Ive lost myself

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Amyloid Plaque
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Questions in 1907
  • What are the plaques made of?
  • Are they killing the neurons?
  • After many decades of work-
  • Plaques are formed mostly from a very small
    protein called Ab42, along with some other
    substances, including, oddly, high metal
    concentrations

11
Cell Culture-Growing a brain in a dish
12
Ab42 added to neurons kills them
13
More questions
  • How is the Ab42 made?
  • How does Ab42 kill neurons?

14
Molecular origin of Ab 1-42
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How does Ab42 harm neurons?Excess Calcium
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How does Ab42 harm neurons?Oxidative Damage
18
Transgenic research
  • Ab42 kills cells in culture, but can it cause a
    disease?
  • Research in the 1990s led to ability to make
    transgenic animals-

19
Brain from transgenic AD mouse
20
The brain as part of a team
  • At 3 lbs, the brain can use up to 25 of the
    oxygen and sugar in the blood
  • The health of the brain is critically dependent
    on the health of the body-especially
  • Cardiovascular health
  • Metabolic state (Diabetes)

21
Brain Activity
22
Cardiovascular and cholesterol
  • Risks High blood pressure, obesity, diabetes
  • Special risk of cholesterol clearance in neurons-
    ApoE4

23
AD Risk associated with ApoE isoform
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Summary of what we know
  • Ab42 is made by a specific cut by the enzyme
    gamma secretase
  • Ab42 then forms into insoluble waxy deposits
    called plaques
  • These plaques are toxic to neurons, causing
  • Increased calcium into the neuron
  • Increased oxidative stress
  • Inflammation
  • This then causes the neuron to get sick, so that
    they release less neurotransmitter and
    communicate less
  • Eventually, the neuron dies
  • The ability of the neuron to resist this depends
    on poorly understood factors of metabolism and
    cholesterol
  • ALL of these factors are targets for drug
    development

34
Current Treatments
  • In 1993- the FIRST drug released for AD
    treatment.
  • Tacrine (Cognex)- Inhibited the breakdown of
    acetylcholine, by blocking the enzyme
    acetylcholinesterase
  • Efficacious for mild to moderate Alzheimer's
    disease
  • Very serious side effects, limited efficacy

35
Cholinesterase Inhibitors
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Other Ach Inhibitors followed
  • Acetylcholine esterase inhibitors
  • Donepezil (Aricept) piperidine-based, reversible
    inhibition of its hydrolysis by
    acetylcholinesterase
  • Galantamine (Razadyne ER/ Reminyl) a tertiary
    alkaloid, is a competitive and reversible
    inhibitor of acetylcholinesterase.
  • Rivastigmine (Exelon ) carbamate-type,
  • Do not improve underlying condition, do not
    increase lifespan

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In 2003, the first drug approved for severe AD-
Memantine
  • Ebixa, Namenda Moderate-affinity NMDA
    (N-methyl-D-aspartate) receptor antagonist.
  • Memantine seems to reduce the entrance of calcium
    through specific channels

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Memantine
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Non-prescription drugs
  • NSAIDS (Aspirin, etc)- Reduce inflammation- delay
    onset and extend function
  • Anti-oxidants (Vitamin E)- Reduce the oxidative
    damage
  • Omega-3 fatty acids-May regulate cholesterol
    clearance and oxidative stress

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Developing a new drugClinical Trial
  • Definition
  • A prospective study that compares the effect and
    value of interventions against a control in human
    beings.

44
Clinical Trials Process of Candidate Drug
Development to Obtain Approval for Patient
Prescription
  • Phase 1 first administration to humans to
    determine the maximum tolerated dose and the
    toxicity in humans
  • Phase 2 to determine the efficacy
  • Dose regime and patient selection
  • Find rate of common serious adverse effects
  • Phase 3 test effectiveness
  • Submission to the National Regulatory Body for
    evaluation and approval
  • Phase 4 Long term observation following
    marketing of approved drug

45
New breakthrough drugs are hard to find
  • Only 10 of compounds reaching clinical trial
    make it to market
  • It takes 10-12 yrs from discovery of new medicine
    until it is available to the patient
  • The average cost for a medicine to get to market
    in 2002 was 800 million (USD)
  • Only 3/10 new products recover development costs

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Drugs in Phase IIIFlurizan
  • Binds to and modulates of g-secretase-Causes less
    Ab42, and more Ab40
  • In this Phase 2 study, most patients were
    receiving acetylcholinesterase inhibitors, thus
    the results are above the current standard of
    care.
  • In nonclinical studies, FLURIZAN reduced Ab42 by
    approximately 70
  • Decrease in the number of psychiatric events and
    the dramatic lengthening in time before patients
    experienced such events

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Flurizan
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Flurizan Phase 2 trial
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Flurizan Phase 2 trial
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Flurizan Phase 2 trial
52
Drugs in Phase IIINeurotrophic agents
  • Xaliproden (SR 57746) and Cerebrolysin
  • Neurotrophins are hormone-like molecules that aid
    neuronal health
  • These drugs mimic natural neurotrophins and may
    increase neuronal resistance

53
Drugs in Phase IIIAnti-inflammatories
54
Ibuprofen (Advil, Motrin, Nuprin)
  • Preventing or delaying the onset of Alzheimer's
    disease by decreasing inflammation in the brain
  • A nonsteroidal anti-inflammatory drug (NSAIDs),
  • NSAIDs help Alzheimer's patients have been
    retrospective.
  • Reduces prostaglandin activity by inhibiting
    prostaglandin synthetase

55
Estrogen (Premarin)
  • estrogen in postmenopausal women may delay the
    onset or risk of AD.
  • antioxidant and anti-inflammatory effects and
    enhances the growth of select neurons that
    release acetylcholine
  • may improve lipoprotein/lipid metabolism.

56
Vitamin E (Alpha-tocopherol )
  • Good dietary sources of vitamin E include
    spinach, eggs, nuts and seeds, avocado, tomatoes,
    peaches, and blackberries
  • recommended 400 IU of vitamin E daily
  • did not appear to help people with a version of
    the apolipoprotein E (Apo E) ApoE4
  • considered to be an anti-oxidant vitamin
  • Also a know anticoagulant

57
Drugs in Phase IIIZocor Lipitor
  • Decreases cholesterol, LDL, triglycerides, and
    increases HDL
  • Seem to inhibit both alpha and beta secretase
    activities in CNS.
  • Also seem to decrease inflammation

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Zocor Lipitor
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Drugs in Phase IIIAvandia (rosiglitazone XR)
  • Diabetes drug- Aids in regulation of blood sugar
  • Appears to provide increased energy to neurons,
    allowing them to resist stress.
  • Is not effective for those who carry the ApoE4
    gene linked to earlier and faster-progressing
    Alzheimer's disease.

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Avandia
61
Drugs in Phase IIITramiprosate (ALZHEMED)
  • Sticks to Ab42, and stops it from forming plaques
  • Dose- dependently reduced CSF A(beta)42 levels
    after three months of treatment.
  • Results consistent with stabilization of
    cognitive function in mild AD patients after up
    to 36 months.

62
Tramiprosate (ALZHEMED)
63
Special Topic Ab Vaccines
  • In this process, a form of Ab, or of amyloid
    plaque, is injected into a person, to they have
    an allergic reaction
  • Theoretically, antibodies are formed against the
    Ab, and this may help clear the plaque

64
Ab vaccine
65
How the vaccine may work
66
Much left to do
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Percival Linc Aulston1907-1993
  • Your greatest triumphs come when you think you
    are most alone.
  • But, you are never really alone
  • THANK YOU

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Nasal Spray
  • Administered via drops in the nose -- that would
    initiate an amyloid-cleansing process by
    triggering the immune system without provoking
    antibody development.
  • Targeted a specific type of amyloid-eating cell
    known as a microglial cell -- stimulating the
    cells into action to essentially gobble up the
    amyloid build-up.

71
Innate immune response to amyloid-ß in
Alzheimers disease
Steps in the inflammatory process surrounding the
amyloid plaques are shown. The production of
complement components (C1q, C3 and C5) is the
first stage in response to amyloid-ß deposition,
followed by migration of microglial cells to the
brain. This is followed by astrogliosis, which is
characterized by increased expression of the
astrocyte marker glial fibrillary acidic protein
(GFAP) in the brain. Both microglial cells and
astrocytes secrete various pro-inflammatory
mediators that exacerbate the process.
72
Clinical trials of amyloid-ß142 immunization
  • An amyloid-ß142 synthetic peptide (AN1792 Elan
    Pharmaceuticals Inc.) was administered with a
    previously tested T helper 1 (TH1)-cell-inducing
    adjuvant (QS21) to individuals with mild to
    moderate Alzheimers disease.
  • Intramuscular injection
  • that nasal vaccination with a proteosome-based
    adjuvant that is well tolerated in humans plus
    glatiramer acetate, an FDA-approved synthetic
    copolymer used to treat multiple sclerosis,
    potently decreases Aß plaques in an AD mouse
    model. This effect did not require the presence
    of antibody, as it was observed in B
    celldeficient (Ig µnull) mice. Vaccinated
    animals developed activated microglia that
    colocalized with Aß fibrils, and the extent of
    microglial activation correlated strongly with
    the decrease in Aß fibrils. Activation of
    microglia and clearing of Aß occurred with the
    adjuvant alone, although to a lesser degree. Our
    results identify a novel approach to immune
    therapy for AD that involves clearing of Aß
    through the utilization of compounds that have
    been safely tested on or are currently in use in
    humans.

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Research Hope
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