Autophagy: From Mechanisms to Medicine

Charbel Moussa, MBBS, PhD

Associate Professor of Neurology
Scientific and Clinical Research Director- Translational Neurotherapeutics Program
Research Director- National Parkinsons Foundation Center of Excellence
Director- Laboratory for Dementia and Parkinsonism
Georgetown University Medical Center
E-mail: cem46@Georgetown.edu

Disclosures
Charbel Moussa is an inventor on a issued patent to use TKIs as a treatment for neurodegeneration
 FACES WE KNOW
Many faces
of beloved
family and
friends we
also know ?
President Reagan Michael J. Fox Lou Gehrig
Alzheimer Parkinson Amyotrophic Lateral
Sclerosis (ALS)
Dementia, including Alzheimers disease (AD):
Number will rise to 50m in 2050
The direct and indirect costs for the dementias was more than $296 b in 2014.

Parkinsons disease (PD)

60,000 Americans are diagnosed every year
Estimated 10 million people worldwide are living with PD

By 2060:
The aging population is projected to increase with over 4% of pop over 85 and almost 22% over 65
The number of people diagnosed with neurodegenerative diseases will reach 100 million
 Misfolded protein aggregates are the culprit in neurodegenerative diseases
Autophagy can clear misfolded proteins

Amyloid Plaques
- Nilotinib is an anticancer drug (tyrosine kinase
inhibitor) which FDA has previously approved for
CML chronic myeloid leukemia.

Tau inclusions - Nilotinib introduces autophagy

- We questioned: if it can remove toxic proteins,

would it work for neurodegeneration?

Alpha-Synuclein
Lewy bodies

TDP-43
(Mathias Jucker & Lary C. Walker, September 2013, Vol 501, Nature, 45)
 Self-propagation of pathogenic protein aggregates in neurodegenerative diseases.
Amyloid Plaques
Tau inclusions
Lewy bodies Mathias Jucker & Lary C. Walker, SEPTEMBER 2013 | VOL 501 | NATURE | 45
-Synuclein
TDP-43
Possible quality control mechanisms for protein
degradation or clearance.
Glial cells

Amino acids
Proteasome

Amyloids;
Tau, A,
-Syn, Prions
Htgs, TDP-43. etc

Route A

Route B

Route C Cell-to-cell propagation

Exosomal/
Golgi/ER exocytosis

Nucleus

Cell 1 Cell 2
TKI (bosutinib) reduces Ab in transgenic mice
TKI improves memory in transgenic FTD-TDP mice
Before treatment

C57BL/6 TDP-43

After treatment

TDP-43+DMSO TDP-43+Nilo TDP-43+Bos

 Based on compelling pre-clinical
evidence we conducted a small clinical
trial to evaluate Nilotinib effects on
safety in Parkinsons Disease Dementia
(PDD) and Lewy Body Dementia (LBD)
6 months treatment.
Nilotinib improves motor function- with
no serious side effects
Parkinsons score -UDPRS
 Nilotinib improves cognition
Mini-Mental Status Exam (MMSE) in PDD and LBD patients
Now enrolling for Phase II, placebo controlled, double-blind
Nilotinib study in Parkinsons disease
Participants diagnosed with PD stage 2.5-3 with MCI

Phase I: Phase II:

Ascertained drug safety Ascertain drug safety
Two ascending doses of Two ascending doses of
Nilotinib with advanced PD/LBD patients Nilotinib with PD

Pharmacodynamics
Pharmacodynamic data: Support target engagement via
Evidence of target engagement via Abl, CSF alpha-Synuclein, Tau, Abeta and HVA
CSF alpha-Synuclein, Tau, Abeta and HVA

Pharmacokinetics
Pharmacokinetic data:
Measure Nilotinib levels in CSF
Measured Nilotinib levels in CSF
to ensure the drug crosses the BBB
Safety/efficacy biomarkers
Measure CSF and plasma levels of
Safety/efficacy biomarkers inflammatory/neurotrophic markers
Identified markers for immunological
and non-immunological effects
Possible clinical outcomes
Now enrolling for Phase II, placebo controlled, double-blind
Nilotinib study in Alzheimers disease
Participants diagnosed with mild to moderate AD

Phase I: Phase II:

Ascertained drug safety Ascertain drug safety
Two ascending doses of
Two ascending doses of
Nilotinib with AD patients
Nilotinib with advanced PD/LBD patients

Pharmacodynamics
Pharmacodynamic data: Verify efficacy via PET imaging and
Supported target engagement via Abl, CSF Tau, p-Tau, Abeta levels and vMRI
CSF Tau, pTau, Abeta

Pharmacokinetic data:
Measured Nilotinib levels in CSF
to ensure the drug crosses the BBB
Safety/efficacy biomarkers
Identified markers for immunological
and non-immunological (neurotrophic) effects
Pharmacokinetics
Measure Nilotinib levels in CSF
Safety/efficacy biomarkers
Measure CSF and plasma levels of
inflammatory/neurotrophic markers
Possible clinical outcomes
 Major questions about repurposing drugs for use in
neurology

1- Drug penetration into the brain

2- CNS target engagement

3- Potential neurotoxicity

4- Transition to clinical development FDA and regulations

5- The role of biomarkers and their clinical significance

6- Drug cost and commercialization

7- The scientific dogma.

 The scientific dogma

It may be non-obvious to scientists that cancer drugs

which kill tumors can also be used to stop neuronal death.

Repurposing of cancer drugs for use in neurodegeneration

challenges the dogma that may often discount the critical
importance of empirical evidence in science.

Cancer drugs kill metastasis, but they may also exploit

molecular mechanisms to achieve opposite outcomes in
neurodegeneration.
 Could cancer drugs be repurposed for use in
neurodegeneration?

Identify molecules that could have new indications for

neurodegenerative diseases

Understand drug actions and mechanisms for repurposing

 Transition to clinical development
FDA and regulations
Proof of concept studies- repurposing and first
in human use
The Investigational New Drug (IND)
Phase I, II and III
New Drug Applications (NDA)
Extension trials and Drug Approval
 Drug cost and commercialization
Health economics may either promote or impede cancer drug repositioning

Clinical trials failure in PD and AD contribute to the public apprehension

This circumspection, although healthy, contributes to many roadblocks scientists face when
repurposing a new drug, mainly via reduced governmental and non-governmental funding

The majority of FDA-approved cancer drugs are under patent protection, raising the level of
difficulty to get a marketed non-generic drug from pharmaceutical manufacturers

Overall patent life triggers reformulation of existing FDA-approved drugs in order to garner
a more profitable and prolonged patent life

This route not only prevents expediting treatments to patients but involves the risk of
failure of a novel compound on safety or efficacy grounds

On the other side of the spectrum, it is estimated that it takes an average of 10 years and
$2.5 billion to develop a new drug (http://www.phrma.org)

Reducing the cost of R&D via repurposing cancer drugs that have known safety and
tolerability profile can significantly expedite treatments to patients, alleviate caregiver
burden and reduce the national socioeconomic cost.
 Conclusions
Cancer drugs represent a novel strategy and a potential disease modifying therapy for
neurodegeneration

They may have compelling preclinical mechanistic, human safety, and efficacy data

Drug repurposing represents a high-yield, short-term return on investment with the

potential to alleviate the suffering of millions of patients.

Expert opinions and hypotheses about the use of cancer

drugs as neurotherapeutics must be subjected to rigorous
scientific experimentation so empirical evidence can
validate or reject the benefits of use of cancer drugs in
PD and AD.
Translational Neurotherapeutics Program
Laboratory for Dementia and Parkinsonism
Movement Disorders Program
Clinical Research Unit
Funding
NIH- NIA, NINDS
Merck Neuroscience Discovery
Novartis Pharmaceutical Corporation
Alzheimers Association
Alzheimers Drug Discovery Foundation
Cure Foundation- Donors Cure
Michael J . Fox Foundation
American Parkinsons Disease Foundation
National Parkinson Foundation
Mucopolysaccharidosis Society
Baragas and Lasky Foundation
Budson and Agger Foundation
Private Philanthropies
Georgetown University
Memory Disorders Program