Defeating Alzheimer disease and dementia when will we get the cure?

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1 Defeating Alzheimer disease and dementia when will we get the cure? Bengt Winblad Karolinska Institutet, Dept NVS Center for Alzheimer Research Div of Neurogeriatrics Huddinge, Sweden Demensdagene Copenhagen, May 7, 2018

2 Extracted from the ADI World Alzheimer Report, August 2015 Acknowledgements Maria Ankarcrona Angel Cedazo-Minguez Susanne Frykman Miia Kivipelto Janne Johansson Francesca Mangialasche Patricia Mecocci Lars Tjernberg Gunilla Johansson Bengt Winblad May 7,

3 - Health economics in AD - Epidemiology - Prevention - Genetic risk - Disease Biology - Diagnosis and Biomarkers - Pharmacological treatment - Non-pharmacological treatment - Formal and informal care - Ethics Bengt Winblad May 7,

4 Disease Pathology NFTs Aβ plaques Bengt Winblad May 7,

5 Disease Biology Hardy et al. JIM, 2014 Winblad et al. Lancet N, 2016 Bengt Winblad May 7,

6 Therapy in AD: The first hundred years and looking forward. Memantine NMDA Uncompetitive Receptor Antagonist The cholinergic hypothesis Acetylcholinesterase inhibitors First Disease Modifying Rx? Amyloid and tau lowering? Bengt Winblad May 7,

7 Ongoing clinical trials in AD β amyloid Tau CAD106 Aß production Aß aggregation Aß clearance Cholinergics Others Mangialasche et al, modified 2013 from Lancet Neurology, 2010

8 Modulating neurotransmission ongoing studies Acetylcholine modulator: Acetylcholinesterase inhibitors, Nicotinic agonists alpha 7 Serotonin receptor modulation 5-HT4 partial agonists, 5-HT1A agonists/antagonists, 5-HT6 antagonists Norepinephrine/Dopamine modulator: MAO A and MAO B inhibitors Glutamate modulation: AMPA potentiators GABAergic modulation: GABA antagonists Glycine: partial agonists MAO=monoamine oxidase; GABA=gamma-aminobutyric acid; AMPA=alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Bengt Winblad May 7,

9 Amyloid-Related Approaches as New AD Treatments APP gene Antisense Si RNA APP Production A monomer Fe, Cu 2+ Chelator: PBT2 Immunotherapy, eg: Solaneuzumab Crenezumab Gantenerumab Aducanumab CAD106 β- and γ- secretase inhibitors & modulators, eg: Verubecestat A oligomer Aggregation Fibrillogenesis Modulators, eg Scylloinositol A fibril Diffuse plaques Courtesy of Dr Norman Relkin, Weill Cornell Medical School, New York, modified 2015 from H Feldman pres Deposition Senile plaques

10 Vaccination Active vaccination with β-amyloid Passive vaccination with β-amyloid antibodies -amyloid -amyloid Immunisation with β-amyloid + immune stimulating adjuvans Mice are immunized with β-amyloid The immune system forms antibodies against β-amyloid The mice form antibodies against β-amyloid Mice antibodies are being humanized The antibodies bind to oligomers and plaques After injection of antibodies, they bind to oligomers and plaques Bengt Winblad

11 Aducanumab (BII037) treatment of AD reduced brain beta-amyloid levels (phase-1-study) BIIB037 is a high affinity fully human monoclonal antibody directed towards Aβfibrils and plaques. The antibody derived from healthy aged whose immune system had successfully resisted AD. ("reversed translational medicine ). 166 persons with prodromal or mild AD were included in a multi-center study. Aducanumab dose dependently reduced the amyloid deposition in six cortical brain regions. The effect remained after1 year. Aducanumab appears to reduce decline on the MMSE and CDR-SB in a dose dependent fashion. Amyloid PET at study start (left) and after 1 year treatmant (right). Sevigny et al. Nature 2016 Bengt Winblad May 7,

12 Tau-Related Approaches as New AD Treatments Tideglusib GSK 3 Inhibitor Treatments Directed at Microtubules Lithium, Valproate and Tau Pathology Davunetide NAP all negative TRx0237 (Rember) - ongoing Epothilone D Paclitaxol Davunetide HDAC Inhibitors Immunotherapy: AADVac1, ACI-35 ongoing Modified from Brunden et al Nature Rev Drug Discovery 2009; Boutajangout et al J Neurosci 2010

13 Tau Vaccine (AADvac1) Immunogenicity Robust immune response Novak et al, Lancet Neurol 2016 Cognition Mean ADAS-Cog score stable over 6 months Bengt Winblad May 7,

14 Complementary to amyloid and tau; next generation targets.. Proteinopathies and Misfolded Proteins Tau -synuclein Htt Neurodegenerative Pathways Neuro-inflammation Protein homeostasis Amyloid FUS TDP-43 PrP Mitochondrial /oxidative damage Axonal/Microtubule dysfunction FUS Amyloid plaques Tangles Toxic Oligomeric Abnormally Folded Aggregate Lewy bodies Ubiquitin aggregates Synaptic dysfunction /Excitotoxicity Vascular/Lipid biology Bengt Winblad May 7,

15 ThT flourescence BRICHOS: an endogenous anti-amyloid chaperone Mutations in BRICHOS proteins give amyloid disease and dementia Recombinant BRICHOS is a potent inhibitor of Aβ40/42 fibrillation and toxicity in vitro and in vivo Structure of BRICHOS proteins BRICHOS Time (h) Willander H et al. JBC,

16 BRICHOS: The first described naturally occurring chaperone that specifically prevents amyloid formation and toxicity Blocks a specific step in Aβ42 fibril formation Prevents CNS toxicity of Aβ42 in vivo (transgenic Drosophila) Is a small protein domain that can easily be produced in bacteria Bengt Winblad May 7,

17 Synaptic degeneration A β ROS One of the earliest pathological hallmarks and the one that correlates best with cognitive decline Molecular mechanism largely unknown Involvement of Aβ, mitochondria, ROS and lipid homoeostasis Intracellular or secreted Aβ? Aβ ROS Synaptic intracellular targeting of β- and γ-secretase inhibitors and antibodies might be more effective Bengt Winblad May 7,

18 Encapsulated Cell (EC) biodelivery The tip of the EC biodelivery system is implanted in the brain of patients. It contains living cells which are genetically modified to produce a therapeutic factor. The membrane enclosing the cells allows the factor to flow out into the patient s brain tissue. Areas deep within the brain affected by disease can be treated to delay or prevent the disease. Bengt Winblad May 7,

19 Research the only way forward to treatment Beta-amyloid Tau Neuroprotection (antioxidants, growth factors) Risk inhibition (clues from genetics & epidemiology) All patients? Only FAD? Treatment for AD APOE Cholesterol Inflammation New findings from basic research Individualization A B C D Definition of disease subtype BIOMARKERS Modified from A Cedazo-Minguez Bengt Winblad May 7,

20 Neurotransm Neuroprotection modulators Next generation targets Amyloid & Tau lowering molecules Risk factors intervention A cocktail of will be the best AD treatment!

21 Acknowledgements Maria Ankarcrona Angel Cedazo-Minguez Maria Eriksdotter Susanne Frykman Janne Johansson Patrizia Mecocci Anders Wimo Gunilla Johansson Bengt Winblad May 7,