This presentation will analyze and present a perspective on some challenges in CNS drug discovery and development, including: where we have been, contemporary neuroscience pipelines, success in CNS drug research, and where to go now.

Axial Biotherapeutics' vision is to establish a new path for targeting neurological disorders through harnessing the power of the gut-brain axis. This radical idea is based on the groundbreaking work of scientific founder, Dr. Sarkis Mazmanian, who was the first to describe a functional link between the gut-brain axis in Parkinson’s disease and the impact of neuroactive microbial metabolites on autism behaviors. These findings contribute to a paradigm shift and a significant scientific advancement in how we approach the treatment of neurological disorders and the departure from the belief that neurological disorders originate exclusively in the brain.

We have created a minimally invasive designer receptor (DREADD) - based therapy platform that can be used to control activity of the circadian neurocircuitry, including locus coeruleus (LC), a deep brain nucleus that is otherwise impossible to access without brain surgery. We utilize the retina as a target for DREADD expression, from which we can manipulate these key neural structures whose aberrant activity characterizes numerous neuropsychological disorders, including major depression, addiction, attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, and sleep disorders. Therefore, this technology has potential applications across several disorders. This presentation will focus on this technology as it applies to depression.

The design of therapeutic agents that penetrate the blood-brain barrier is challenging mainly due to the promiscuity of efflux transporters. The structures of P-gp and BCRP have been published, allowing us to build machine learning models that combine the transporter structural information with traditional ligand-based descriptors. The performance of these models will be presented.

Molecular imaging, such as PET, has been widely used in medical research and drug discovery. We have developed new imaging tools and applied them in clinical research and drug discovery. In this presentation, I will discuss the development and application of molecular neuroimaging techniques for brain research. Our work is a unique example on the multidisciplinary research, including molecular imaging, medicinal chemistry, clinical research, and preclinical drug discovery.

Neuroinflammation is a pathological hallmark of CNS degenerative diseases, yet preclinical translational tools to support drug discovery programs are lacking. Tiaki has developed an ex vivo slice culture and an animal model that manifests a neuroinflammatory state that is aligned with Alzheimer’s and Huntington’s diseases. Using these tools, a novel anti-inflammatory target for neurodegenerative disease which was identified using curated human data, has been progressed to lead optimization.

TANGO uses antisense oligonucleotides (ASOs) to prevent naturally occurring, non-productive splicing, and increase productive mRNA and fully functional protein. We identified non-productive events in > 50% protein-coding genes. ASOs targeting these events lead to increased mRNA and protein in a dose-dependent manner. TANGO-ASO treatment of Dravet syndrome mice lead to protein restoration to near normal levels, significant reversal of the survival phenotype, decreased seizure frequency and increased numbers of seizure-free mice. 

RNA-binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle, resulting in various molecular phenotypes, such as aberrant RNA splicing, transport, and stability. Emerging therapeutic approaches to mitigate or reverse alterations of RNA-binding proteins in neurological diseases are discussed.

Alzheimer’s disease (AD) is an ageing-related neurodegenerative disorder. It is the primary cause of dementia in the elderly and presently no effective therapeutics are available to modulate disease progression. Genetics have identified not only mutations in specific genes that are linked to the familial early onset form of AD, but also the cause(s) of the more typical late onset form of the disease. Studies have identified new molecular mechanisms and modifiable risk factors of AD, which may enable the development of effective interventions to prevent or cure the disease. Emerging research has shown that the disease can be potentially prevented; and an increasing number of researchers are developing therapies that can modify disease pathology or risk. This talk will be focused on recently identified molecular mechanisms of AD, and translational potentials of developing effective therapeutics of AD.

Ataxin-2 has been identified as a potent modifier of TDP43-toxicity. We demonstrated that knockdown of Ataxin-2 or inhibition of Ataxin-2 interaction with TDP43 effectively reversed TDP43-induced toxicity in hu-iPSC neurons. Proteomic analysis was also performed to identify a specific set of proteins associated with the aberrant Ataxin-2/TDP43 interaction. These findings led us to explore various approaches and modalities that can be used as novel strategy for therapeutic intervention.