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Roadmap to Successful Therapies for Neurodegenerative Diseases

  • Alzheimer’s disease develops because of a complex series of events that take place in the brain over a long period of time.
  • Today, Alzheimer’s disease is typically diagnosed once symptoms are already clinically present meaning it is often diagnosed at later stages of the disease where irreversible loss of neurons has already occurred. This may go some way to explaining recent research challenges.
  • In response, AC Immune has developed a five point Roadmap to Successful Therapies for Neurodegenerative Diseases. As a strategic leader in the field of neurodegenerative diseases, our Roadmap recognizes the importance of treating earlier, targeting Tau, focusing on more homogeneous populations, precision medicine and exploring neuroinflammation as a target.

(1) Reardon S, Nature 2018; (2) Pontecorvo MJ, et al., Brain 2019; (3) Gordon BA, et al., Brain 2019; (4) Positron emission tomography; (5) Strydom A, et al., Alzheimers Dement (N Y) 2018; (6) Lott IT and Head E., Nat Rev Neurol 2019; (7) Robinson JL, et al., Brain 2018; (8) Heneka MT, et al., Nat Rev Neurosci. 2018; (9) Wang S, et al., Int. Immunopharmacol. 2019; (10) (NOD)-like receptor protein 3; (11) Apoptosis-associated speck protein containing a CARD

Treat earlier

It is now believed that treatments targeting amyloid beta (Abeta) may be most effective before symptoms become apparent. The challenge remains, how to identify such individuals within the population. This places a focus on the Alzheimer's Prevention Initiative (API) trial of crenezumab, to answer the fundamental question of whether Abeta monotherapy will work and if Alzheimer's disease can be prevented. Through this work, it may be possible to identify biomarkers that could lead to the development of preventive medicine for use in the wider Alzheimer's disease population. This has the potential to create a situation with parallels to cardiovascular disease where cholesterol is used as a biomarker and statins are prescribed in a preventative mode.

Target Tau

It is well understood that Tau plays a very important role in neurodegeneration, and the question we are asking is whether the Tau cellular machinery in early or mild Alzheimer's disease is already so advanced it cannot be stopped by monotherapy. This is being addressed through multiple Tau research programs in early and late stage disease including small molecules intervening at the first step of Tau pathology inside the cell, a key differentiator in our research strategy.

More homogeneous populations

The role of Abeta has been a significant focus of research however the challenge remains that multiple pathologies are thought to contribute to the development of Alzheimer's disease, including genetic, lifestyle and environmental factors. Patient etiology can be diverse. Therefore, to understand if a candidate drug has therapeutic potential, it is important to identify more homogeneous genetic patient populations. This includes PSEN1 E280A mutation carriers with Autosomal dominant Alzheimer's disease in Colombia and individuals with Down syndrome.

Precision medicine

Building on the understanding that multiple pathologies contribute to the clinical presentation of Alzheimer's disease, there is a need to accurately diagnose the underlying pathology, and, as such, therapeutic strategies may need to be adapted using precision medicine. This builds on our development of specific PET tracers and therapies for the described proteinopathies (i.e. Tau, alpha-synuclein and TDP-43, and selection and treatment of study population according to those dominant proteinopathies).

Target neuroinflammation

It is well established that microglia maintain a healthy brain environment by clearing debris, including misfolded Abeta, Tau and a-synuclein. Hyper-stimulation of microglial cells is now emerging as a hallmark of AD – and could prove a common pathology underpinning all neurodegenerative diseases. Our discovery programs are focused on microglial balance through the NLRP3 pathway by small molecule inhibitors and antibodies which neutralize components of the NLRP3 pathway.