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© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner
Rejuvenation of the Aged Brain
An Example of Drug Delivery in Drug Repurposing
Ludwig Aigner
IntelGenx, Grand Opening, Saint-Laurent, May 10th 2016
YESTERDAY
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 2
TODAY
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 3
TOMORROW
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 4
5
Age: Risk Factor Number 1
Teresa Niccoli , Linda Partridge, Ageing as a Risk Factor for Disease, Current Biology, Volume 22, Issue 17, 2012, R741 - R752
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 6
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 7
Massive Increase in the Prevalence of AD
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 8
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 9
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 10
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 11
GeneticNon-Genetic
Alt
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 12
Alzheimer Pathology
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 13
Are We Targeting the Right Thing ?
Rodrigue et al., Neuropsychol Rev. 2009
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 14
1001 Reasons for Neuronal Cell Death ???
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 15
Neurodegenerationeg Schapira et al. 2011
Neuroinflammationeg Hirsch et al. 2009
Blood Brain Barriereg Zlokovic et al. 2008
Neurogenesiseg Regensburger et al. 2014
Neurotransmissioneg Calabresi et al. 2007
Our Targets:
Pleiotropic Signaling
Demyelination
Axonal Damage
eg Franklin et al. 2008
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 16
AGING and REJUVENATION
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 17
Neurodegenerationeg Schapira et al. 2011
Neuroinflammationeg Hirsch et al. 2009
Blood Brain Barriereg Zlokovic et al. 2008
Neurogenesiseg Regensburger et al. 2014
Neurotransmissioneg Calabresi et al. 2007
Demyelination
Axonal Damage
eg Franklin et al. 2008
The Aged Brain is a „Diseased“ Brain
Regeneration
Disease RiskDisease Risk
Live = Aging
Growth Plasticity Degeneration Disease
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 18
Growth Plasticity Degeneration
Aging and Rejuvenation
„Regenerative Pharmacology“
Disease
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 19
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 20
Can We Turn Back the Clock ?
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 21
Muscle Research, Aging, and Regenerative Medicine ?
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 22
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 23
inflammation
neurogenesis
cognitiion
Modulating the Systemic Milieu: a Valid Approach
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 24
Eotaxin Reduces Neurogenesis
Eotaxin Worsens Cognition
Old Blood Contributes to Brain Aging
EOTAXIN
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 25
Eotaxin Leukotrienes
Allergy / Asthma Brain Aging
Aging / Degeneration
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 26
Leukotrienes Impact on Brain Aging
Leukotrienes
Neurodegenerationeg Schapira et al. 2011
Neuroinflammationeg Hirsch et al. 2009
Blood Brain Barriereg Zlokovic et al. 2008
Neurogenesiseg Regensburger et al. 2014
Neurotransmissioneg Calabresi et al. 2007
Demyelination
Axonal Damage
eg Franklin et al. 2008
Monte
lukast
Proof of Principle:
Inhibition of Leukotriene Receptors Improves Cognition in Aged Rats
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 27
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 28
symptoms pathology therapy
motoric dopaminergic cell loss dopamine replacement
60%
Parkinson´s Disease Dementia / Lewy Body Dementia
symptoms pathology therapy
motoric dopaminergic cell loss dopamine replacement
dementia ??? rivastigmine
Neurogenesis
Blood Brain Barrier
Neuroinflammation
Neurodegeneration
Neurotransmission
eg Schapira et al. 2011
eg Hirsch et al. 2009
eg Zlokovic et al. 2008
eg Regensburger et al. 2014
eg Calabresi et al. 2007
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 29
**
Learning Memory
*
Montelukast Improves Cognitive Functions in PD / LBD Animals
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 30
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 31
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 32
1 1 2 2 1 1 2 3 3 4 3 2 2 4 4 2 3 3 6 7 6 11 714
7 13 15 12 15 19 17 23 25
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Nu
mb
er
of
Pu
blic
ati
on
sAnnual Counts of Publications “Drug Repurposing”
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 33
“All De- and Regenerations are Similar”
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 34
REPAIR
REPLACE
RESTORE
REGENERATE
REJUVENATE
Regenerative Medicine
All Organs
Different Diseases
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 35
MMSE 13: moderate to severe dementia
Montelukast as an Anti-Dementia Therapeutic
Before After 2 Months of Montelukast
MMSE 22: mild dementia
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 36
Discover
y
Preclini
c
Phase
I
Phase
II
Phase
III
Approval
BIOTECH
Academia Big Pharma
© Paracelsus Medizinische Privatuniversität | Institute of Molecular Regenerative Medicine | Ludwig Aigner 37
Let‘s make a better Montelukast