Of Worms and Cells - the power of live animal phenotypic screening in drug discovery

At Ora Biomedical, our approach to drug discovery and development is different. In order to best target aging, we perform unbiased, phenotypic screening in live animal models. We take geroscience seriously by rapidly testing lifespan extending interventions across age-associated and rare disease models to fully realize the potential of longevity therapeutics. We start where it matters, at aging and disease physiology. This is in contrast to typical approaches in drug development that start with target-based screens in cultured cells. What do these two approaches amount to and why is the Ora Biomedical approach a valuable alternative?

What is the difference between target- and phenotype-based screening?

Target-based screening

Target-based screening takes what we think we know regarding molecular mechanism and then develops assays for a specific target. These assays are typically performed in cell culture, as opposed to live animal, models. Once hits that impact the target are identified, validation studies are performed to understand how the intervention impacts the relevant aging/disease state in animals. The approach can yield effective therapeutics, but only if it is correct that the target is a main effector of the underlying condition – an assumption that often proves faulty.

An example: Alzheimer’s disease

The approach to Alzheimer’s disease (AD) therapeutics development is a typical example of target-based drug development. One of the earliest features of AD that was described was the accumulation of amyloid beta (Aβ) plaques within neurons of patients. Indeed, Aβ accumulation is a necessary feature of the disease and an AD diagnosis cannot be verified until the cerebral cortex is analyzed postmortem for these plaques. In the 1990s, the cellular mechanism that generates Aβ was described. Since that time, AD therapeutics development has largely focused on targeting Aβ, both in terms of its generation and clearance within cells. While this would seem to be the right approach, the history of failed clinical trials for AD therapeutics shows the limitations of target-based approaches. Today, the few FDA approved AD “therapeutics” on the market are the subject of intense criticism and limited patient benefit.

Translational research suffers when scientists impose their view of disease mechanism on complex disease states. A biological principle often ignored in drug development is that biology is smarter than you. It is simply hubris to say that we understand what is of primary importance in complex biological systems like aging and age-associated disease.

The question then is, what is a better approach to identifying longevity and disease therapeutics? We believe the answer lies in phenotype-based screening.

The Ora Biomedical approach

We begin our drug development pipeline with unbiased drug screening in live animal models of aging and disease. Instead of stipulating what is important for a condition, we let the biology tell us what matters. We do this by screening interventions in the nematode C. elegans, colloquially referred to as “the worm”. C. elegans is a key workhorse in biology of aging with multiple highly evolutionarily conserved aging mechanisms shared between it and mammals. We use the WormBot-AI, our proprietary robotics combined with machine learning phenotype analysis, to exponentially increase our rate of drug discovery. Hits we identify are screened separately and in combination with known longevity interventions across our disease model panel of age-associated and rare diseases. These disease-specific indications inform our mammalian validation strategies and create multiple pathways into the clinic. This strategy isn’t just a hypothetical approach: we have already identified novel drug hits for further development using our method.

The power of Ora Biomedical

At Ora Biomedical, we can rapidly screen hundreds of thousands of small molecules for lifespan and healthspan directly. This creates the opportunity to find new, far more effective, therapeutics that would not otherwise be discovered. Our method of phenotype-based screening starts with targeting the condition in question, agnostic of what we assume is key mechanistically. What would you rather have, an intervention that targets a particular mechanism or a therapeutic that works? For us, the answer is clear.

‘Ora’ is translated as healthy, alive in Pascuan, the language spoken by the people of Rapa Nui, or Easter Island. This island is known to biologists of aging as the home of rapamycin, a compound with remarkable anti-aging properties in laboratory model systems and currently in clinical trials to become the first broad use gerotherapeutic.

Ora Biomedical, Inc. seeks to realize the full potential of healthy aging therapeutics by developing a new generation of broad use small molecule healthy aging interventions for humans, companion pets, and all other organisms for which prolonged healthy survival is desired. Information on this website pertains to preclinical or clinical candidates in development and has not been reviewed or approved by the Food and Drug Administration.