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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

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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

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