There are more than 7,000 known rare genetic diseases that collectively afflict more patients in the United States than diabetes, but only 5% of these diseases have any effective treatment. A major driver of this lack of therapies is that about 75% of rare genetic diseases cause cognitive and behavioral impairment, which are difficult to recreate in the drug development process. Testing drugs for cognitive or behavioral effects requires a whole-organism model, and mice – the most common animal model – are expensive and take a long time to develop to maturity, preventing them from being a viable option in early drug development and dissuading companies from entering the rare disease space. Many rare diseases lack animal models altogether, and the cost and time to develop one can be prohibitive, whether for a foundation wanting to repurpose existing drugs for a given disease or a pharmaceutical company aiming at a high-value market for new drugs.
CogniXense is a target-agnostic drug discovery platform that enables repurposing drugs for rare genetic diseases in record time. By combining human data-based computational drug prediction with on-demand animal model development, we can mimic the diversity of symptoms of patient populations and begin drug screening on new diseases within a month. Models’ neurological and behavioral functions are measured via an automated, high-throughout instrumentation method that includes testing their ability to learn and navigate simple mazes, facilitating the discovery of drugs that can treat diseases with complex symptoms that are otherwise difficult to target. As a result, the CogniXense platform can be used to quickly identify effective treatments in whole organisms without any prior knowledge of the disease beyond the affected gene or genes. These drugs can be then be repurposed or further reformulated for optimal delivery, and to enable the identification of novel drug targets.
Case study: Rett syndrome
To demonstrate the value of the CogniXense platform, we generated a frog model of Rett syndrome by using CRISPR, a gene-editing tool, to disrupt the MeCP2 gene that underlies the condition. By injecting MeCP2-targeted CRISPR into cells of freshly fertilized Xenopus laevis embryos, we created a population of Rett syndrome-like tadpoles that displayed a wide range of phenotypes, despite relatively consistent average levels of gene disruption. Using the transcriptome of this model, we predicted that specific drugs would reverse the effects of MeCP2 disruption and then screened them in the tadpole model, comparing them to trofinetide (the most advanced drug for Rett syndrome, which is currently in Phase 3 clinical trials). We observed better performance from our top candidate both in terms of tadpole behavior and lifespan. This compound was then taken into a pre-clinical mouse model of Rett syndrome, where it demonstrated comparable efficacy to trofinetide. We are now identifying the drug target responsible for the efficacy of this compound, and in parallel, we are exploring reformulation of the repurposed drug for improved dosing in patients.
The team at the Wyss institute has significantly de-risked the CogniXense technology, and is currently seeking foundation and industry collaboration and venture capital investment to assist with its commercialization.