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It’s no secret that neurodegenerative diseases (Alzheimer's, Parkinson's, ALS and others) typically occur when there is a gradual loss of neurons and a corresponding decline in function, typically resulting in cognitive and behavioral impairments. Each disease type differs from the others, has its own unique features, and many share several hallmarks such as deposition of amyloid fibrils, ROS generation, mitochondrial dysfunction, neurotoxic oligomers, neuronal inflammation, and metal accumulation. The question is, when will we have the full complement of therapies to support patients who are managing these and other less well-known diagnoses? 

Developing new therapies for neurodegenerative diseases – both well-known and rarer ones – involves targeting the underlying molecular and cellular mechanisms driving these diseases. But the challenges of getting new therapies to patients are numerous and complex, requiring scientists and entrepreneurs to make scientific advances while building a business and getting their therapies through clinical trials. With those known facts as a backdrop, LabCentral recently convened our inaugural Mind Matters Scientific Symposium, focusing this initial deep dive gathering on the many aspects of neurodegenerative diseases.  

In concert with esteemed academics, scientists, physicians and entrepreneurs, we explored the pre-clinical, clinical and fundraising landscapes around these devastating diseases. We were honored to host a thoughtful, savvy and committed group of leaders and experts who dove into numerous facets of life-changing diseases that affect 7 million patients in the US alone. [Link to full agenda here] 

The perspectives offered across the keynotes and panel sessions ranged from designing inclusive and diverse clinical trials to implementing combinatorial approaches for clinical success to overcoming challenges with preclinical models. Each challenged conventional thinking and provided a window into some of the latest areas of investigation, as well as exploring the funding landscape. Here’s a look of some of what was covered across the day.  

Therapeutic Developments 

Some of the current strategies for therapeutic development included:  

• Restoring mitochondrial function (solving for mitochondrial dysfunction and oxidative stress, etc.) 

• Targeting Protein aggregation and misfolding (solving for amyloid-beta; alpha-synuclein, etc.) 

• Modulating Inflammation (solving for microglial activation, etc.) 

• Gene therapy (solving for correcting APOE4, toxic protein production, etc.) 

• Targeting disease-specific pathways (solving for tau hyperphosphorylation and aggregation, etc.) 

Inclusive Clinical Trials 

In their opening keynotes about ensuring representation in clinical trials, Holly Massett, PhD (National Institute of Health/National Institute on Aging) [BIO] and Tamiko MaGee-Rodgers, PhD (Global Alzheimer’s Platform) [BIO], started the day with sound advice for researchers in all organizations. They both advocated building clinical trial plans to address the populations most affected. For example, Dr. Massett shared that ADRD (Alzheimer’s Diseases and Related Dementias) risk across populations is drastically skewed for Hispanic and African Americans in U.S. So, if you consider that 50% of the success of a clinical study comes from the quality of the recruitment plan (trial design and protocol development; trial feasibility and site selection and recruitment communication planning), it stands to reason that US studies should include strong representation from both Hispanic and African American populations.  

Dr. MaGee-Rodgers then shared examples of successful site-selection strategies to support the goal of greater representation. They included: 

• Locating sites as close as possible to the population of interest 
• Ensuring that all communication tools are multi-lingual and user friendly 
• Establishing a community advisory committee, and  
• Partnering with local providers and community organizations.  

Alzheimer’s Clinical Trials 
Dana Hilt, MD (Actinogen) [BIO] shared that ‘neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease have significant and disproportionate disability and mortality impacts, especially after the age of 50 when the fractional burden of neurodegenerative diseases dramatically increases compared to other conditions.’  While the economic burden of Dementia is twelve times that of cancer, it’s also colored with the perceived challenges of developing central nervous system (CNS) therapies, influencing several large pharma companies to scale back their CNS programs. ‘Biotech has filled in the discovery and early development gap. However, advances in biomarker technology, imaging, genetics, and other tools are sparking pharma interest again.’  

With the recent FDA approvals for monoclonal antibodies (mAb), amyloid removal to the threshold level provides some benefit despite cost, clinical burden and safety concerns. And there continues to be a large unmet need for alternative therapies. There are 160 ongoing clinical trials on Alzheimer’s Disease (AD), the majority of which are disease-modifying therapies with a smaller population of cognitive enhancement and neuropsychiatric drugs.  

Drug Discovery and Therapeutic Innovations in Alzheimer’s Disease 
Moving from clinical trials to the latest in advancement in drug discovery, Prof. Dennis Selkoe [BIO] gave a brief history on the identification of amyloid plaque accumulation as a molecular pathology of AD and how it led to today’s amyloid lowering therapies. Despite achieving clinical success, these therapies can potentially be more effective as a combination therapy along with up-and-coming approaches such as anti-inflammatory treatments.  

Prof. Li-Huei Tsai [BIO] summarized the findings on the genetics of AD; the connection between risky genes and lipid metabolism regulation. One of the key players, APOE is a self-sustained neuro-glial lipid/cholesterol transport. Tsai’s lab is working on APOE4, one of the versions of the APOE gene that increases the AD risk by 3-fold with one copy and 10-fold with 2 copies. Her research centers on understanding the pathogenicity of APOE4 in iPS cells and post-mortem brains to further develop a molecular hypothesis. There are currently several clinical trials with gene therapies targeting APOE mechanism.  

In Summary  
We concluded with poster presentations from early-stage start-ups and established academic labs, which provided great wrap up to the thought-provoking day. Our collaborators (Alzheimer’s Association; Rainwater Foundation; ADDF) and sponsor (Bayer) contributed their expertise, outreach and hospitality, for which we are most grateful.  

We are enormously grateful to everyone who made this day a success - from keynote and panel speakers to poster presenters, audience members (in-person and virtual), and our sponsor and co-host, Bayer. The flow of ideas, hypotheses and fruitful conversations were all aligned around a common goal: how to get to the patient. A few of the day’s key takeaways: 

• Numerous opportunities exist to reduce the patient burden by utilizing up-to-date technical advancements, particularly digital biomarkers, which are important and necessary due to their ease of access. 
• We need to develop better preclinical models for human relevant predictions. 
• Regulatory bodies need to vet new developments more quickly in order to accelerate iteration cycles and get to patients more quickly.  
• Getting early feedback from venture capital is always beneficial for making connections, generating candid feedback on improvements, and charting a course for future fundability.  

Stay tuned as we share additional material from the live recording on our LabCentral YouTube channel.