Shushant Jain, PhD, is a molecular and cellular neurobiologist who directs Ncardia’s drug discovery team. He is empowering drug developers by designing robust in vitro phenotypic assays in representative model systems to improve the translation of therapeutic strategies. Sushant holds a rich diversity of expertise, having led extensive, multiyear research programs to aid several drug discovery initiatives in numerous therapeutic areas using automation and high-content methodologies.
Dr. Shushant Jain, Director of Discovery Technology
Misfolding and accumulation of proteins has been shown to be the primary and/or secondary driver of neurodegenerative disorders (NDDs) such as Alzheimer’s Disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), among others, also categorized as proteinopathies.
Despite the dedication of drug innovators, numerous therapies designed to prevent or eliminate protein aggregation have faced setbacks in the past. However, these setbacks have not been in vain, as they have yielded invaluable insights that can now inform and guide new and promising drug discovery programs.
In this interview, Dr. Shushant dives into the major past learnings driving progress and explains how to develop innovative and more effective strategies to advance treatments for proteinopathies.
Dr. Shushant, looking backwards, what are the major learnings that will help advance new treatments for proteinopathies?
Well, one of the major learnings is knowing that drugs must target early stages of aggregation (e.g oligomeric or soluble aggregates) and potentially target multiple mechanisms to be effective against protein aggregation. For example, targeting both Aβ and TAU for treatment of Alzheimer’s disease may represent a better strategy than targeting Aβ or TAU individually.
Another important learning that came from failed clinical trials highlighted the relevance of patient selection. Clinical scientists need to define patient subgroups that are more likely to respond to specific therapies. Therefore, moving into personalized treatment approaches holds great potential to improve patients’ lives.
Furthermore, I’d like to point out the relevance of open collaboration between researchers, clinicians and industry to expedite progress. Thanks to these collaborations we have gained a better understanding of the underlying disease mechanisms, patient to patient variability and been able to designed novel therapeutic strategies.
Historically, the ‘one disease–one target–one drug’ approach has been predominantly used. What innovative strategies have you seen emerging with potential to bring life-changing therapies?
While the ‘one disease–one target–one drug’ approach can render positive outcomes for mono-target, monogenic diseases, for multifactorial ones, such as neurodegenerative disorders, this approach falls short. In this field the multi-pronged approach is gaining popularity. This is a combination of different strategies and techniques used to address various aspects of the disease process simultaneously.
When the underlying mechanisms of a disease are well understood, it is possible to develop better therapies. For proteinopathies in particular, as protein aggregation is a shared hallmark for several NDDs, developing drugs to prevent or eliminate these aggregates can potentially lead to an effective treatment for several disorders. You can think of one drug acting on various proteinopathies or multitargeted drugs tackling key underlying mechanisms for one or more diseases.
The development of proteasome or lysosome activators is one promising investigational line. This strategy leverages the natural clearance system of the cells to degrade misfolded or aggregated proteins. Another strategy is the development of multitargeted drugs or broad-spectrum compounds aiming to reduce oligomerization, the early stages of aggregation, for more than one pathological protein.
Moving into a different disease factor, neuroinflammation is also playing a critical role in neurodegeneration and it is associated with multiple brain diseases. Therefore, many therapeutic developers are focusing in finding drugs that can modulate the brain immune response (astrocytes and microglia), to slow down progression of several NDDs.
Those innovative approaches you have described are promising, but, as you know, innovation comes with challenges and risks that must be addressed. According to you, what type of resources would be needed to advance those innovative therapeutics with confidence?
As we have learnt in the past decades, one of the major reasons for failure is the lack of translation from target discovery to clinical trials. In order to improve the chances of success with innovative strategies, we need to maximize the physiological relevance of the assays as early as possible.
Throughout the drug discovery process, developers try to solve different scientific questions that would lead to the ideal drug candidate. But, what is the model system and assay set up that is going to give you the most accurate answer to your scientific question? That’s the key to increase confidence and success.
Unfortunately, for NDDs the answer is not easy to find as, in many cases, the available models do not properly mimic disease pathology. As Director of Discovery Technology at Ncardia, we work every day to tackle this major issue and provide drug developers the answers they need.
All our assays are based on human induced pluripotent stem cell technology and, with our expertise, we can make this technology robust, allowing its use in all stages of the drug discovery process. Additionally, we are very much focused on designing robust assays that enable our clients make data-driven decisions and mitigate risk of late stage failure.
As an example, we have recently launched the Proteinopathy Exploration Package. This is a suite of drug discovery assays that puts together the latest understanding of disease and human iPSC technology to catalyze the identification of drug candidates targeting protein aggregation.
Unlike traditional methods, this assay suite assesses drugs’ ability to prevent or eliminate the aggregation of key proteins associated with prevalent NDDs: TAU, α-Synuclein, and TDP-43; as well as potential downstream detrimental effects of protein aggregation (e.g. neuronal damage or electrophysiological function). The insights derived from this package can significantly increase the confidence in the development of specialized drugs, such as protein degraders and/or multitargeted therapies. In addition, by screening three models in parallel, we can speed up progress and increase the understanding of drug’s effectiveness in diverse human contexts.
In summary, as described by Dr. Shushant, the hurdles facing transformative therapies for neurodegenerative disorders are undeniable. Yet, Ncardia’s commitment lies in empowering drug developers to surmount conventional model limitations through the smart application of human induced pluripotent stem cell technology.
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