Our Scientific Approach
Curetopia is a BioDAO initially focused on the funding and coordination of projects that utilize drug repurposing as a promising approach to accelerate the discovery of potential treatments for rare diseases. Our partner laboratory, Perlara PBC, conducts screening of yeast-patient avatars against an extensive library of existing drugs approved for other indications - including nutraceuticals and over-the-counter supplements like vitamins - that have the potential to illuminate breakthrough treatments for rare diseases where previously there was little hope.
Disease Modeling in Yeasts
Yeast drug repurposing screens represent an unprecedented advancement in the field of drug discovery, leveraging the unique strengths of Saccharomyces cerevisiae as a model organism. The conservation of metabolic pathways between yeast and humans makes S. cerevisiae an ideal system for studying complex biological interactions. The extensive characterization of each gene and protein interaction within yeast provides a level of detail that is often challenging to achieve in more complex model systems. Despite these advantages, yeast is frequently overlooked in favor of higher organisms, primarily due to its perceived simplicity. However, this simplicity enables the intricate and precise exploration of conserved pathways, offering unparalleled insights that are difficult to capture in more complex models.
Here’s how it works:
First we confirm that yeast have an ancestral version of a human disease gene. Because yeast have been poked and prodded in the lab for decades, many of the rare disease genes we seek to model in yeast have already been studied.
In almost all cases we can leverage already existing yeast avatars that were generated and characterized by academic labs, sometimes as long as two decades ago. When necessary, we can dial in a specific mutation at practically any location in the yeast genome using gene engineering techniques that predate CRISPR-Cas9.
We have had great success with a 8,400-compound drug repurposing library called TargetMol, which offers a wide selection of clinically actionable compounds including generic drugs and over-the-counter supplements/nutraceuticals.
In every yeast-powered screen we've completed on behalf of individual families or foundations to date, we've identified an over-the-counter option that parents could act on in consultation with their doctors. This is "1-to-N" aka community medicine.
In 2019, drug repurposing screens that used invertebrate-patient avatars, followed by hit validation in patient fibroblasts, yielded the discovery of epalrestat — a potential treatment for PMM2-CDG (Ligezka et al., 2021; Iyer et al., 2019).
This discovery culminated in a pivotal clinical trial in pediatric PMM2-CDG patients, spearheaded by Maggie’s Pearl—a joint venture between our partner laboratory Perlara and a pioneering PMM2-CDG family dedicated to advancing epalrestat to the global market.
Subsequently, Perlara's yeast-based drug discovery pipeline has identified clinically relevant candidates for over 20 rare diseases, with many currently undergoing evaluation in 1-to-N observational studies, highlighting the pipeline's transformative potential in addressing rare disease challenges (Thevandavakkam et al., biorXiv, 2024).
Developing treatments for rare diseases presents unique challenges, but also unexpected opportunities. The mega-blockbuster heart-disease-prevention drugs called statins were originally approved as cholesterol-lowering agents for a rare genetic form of hypercholesterolemia.
The high costs, long timelines and risk aversion of TradBio drug development are mismatched for tiny, fragmented, and globally distributed rare disease communities that are nonetheless highly motivated to move ultra-fast and operate ultra-lean. Many rare disease families have taken the initiative to fund research efforts, but this one-at-a-time approach is neither scalable nor sustainable for widespread therapeutic development.
Decentralized Science (DeSci) represents a bold break from the Academia-VC-Pharma complex that has dominated drug development for decades, but has woefully underserved the 1 in 10 people on Earth who are living with a rare disease. Curetopia imagines a future where members of patient communities and allies, including patients themselves, have control of the direction of research that personally affects them, as well as stakeholder status in the outcome in exchange for their advocacy, biosamples, data, and participation in clinical trials.
Scientific Roadmap
We have prospectively identified nearly 800 inherited metabolic diseases – 8% of all known rare diseases – that are caused by loss-of-function mutations in evolutionarily conserved genes whose deficiency can be faithfully modeled in yeast. We have further mapped these diseases onto entire pathways. We propose to assess the effects of thousands of repurposable drugs and nutraceuticals on the growth of 60 yeast models of inherited metabolic diseases using our established yeast screening pipeline to encompass entire pathways.
The resulting first-of-its-kind drug repurposing and biomarker discovery will be queried within minutes of a genetic and biochemical diagnosis – ideally while a newborn is still in the NICU – and return high-confidence drug repurposing recommendations for each inherited metabolic disease. The resulting predictive drug repurposing recommendations will be able to capture significant value via multiple commercialization approaches, analogous to OpenAI creating an index (database) of all Internet content with which to train ChatGPT.
Our proposed go-to-market strategy combines FDA approval-seeking clinical development with partnerships with nutraceutical manufacturers and compounding pharmacies to sell proprietary combination therapies directly to consumers. Ultimately, insurance companies, hospital systems and governments will reimburse costs because a drug repurposing standard-of-care database for inherited metabolic diseases will yield significant pharmacoeconomic savings. This model will also promote economic growth outside the healthcare system by enabling caretakers to return to the workforce and giving patients the chance to live fulfilling and productive lives.
Meet our Science Officers
Ethan is the founder and CEO of Perlara PBC, the world's first biotech Public Benefit Corporation established in 2014, and a YC company (W16). Ethan is also the cofounder and CEO of Maggie's Pearl, a family-led, clinical-stage biotech. He started using yeast as a therapeutic platform in graduate school at Harvard University in the lab of Dr Stuart Schreiber, and later as a Lewis-Sigler Fellow at Princeton University.
Kristin Kantautas is a Cure Guide and Director of the Congenital Disorders of Glycosylation Program at Perlara. With a background in molecular genetics and glycobiology, she specializes in translating scientific discoveries into clinical therapies for rare metabolic diseases. Since 2022, she has led 10+ drug repurposing programs, advancing treatments to the clinic and building strategic partnerships.
Director of the Yeast Drug Repurposing Program, pioneering therapeutic innovations for rare diseases. With expertise in synthetic biology, yeast models, & translational research, she has led ~20 repurposing pipelines since 2022, advancing candidates for patient studies. A catalyst for biotech innovation, she bridges science and patient-centered care to revolutionize treatments for underserved communities.
As Mitochondrial Disease Program Director at Perlara, Shiri leads patient-centric drug repurposing initiatives for mitochondrial disorders. With 20+ years of experience in academia and industry advancing protein production, drug discovery, and delivery, she is dedicated to finding effective treatments, improving outcomes, and accelerating therapies that make a lasting impact on patient lives.
Recommended Reading
A rebel alliance of rare parents united as the PIGN-CDG Cure Collective to fund a drug repurposing project. One of the top 3 hits is ascorbyl palmitate aka fat-soluble vitamin C - and it's working!
The unlikely intersection of overlooked diseases, overlooked assets and overlooked founders is the place we've called home for the past 10 years. When enough droplets come together they form an ocean.
All therapeutic interventions start with a medical pioneer suffering from a disease, big or small. Let's focus less on the total number of patients and more on specific humans as living laboratories.
What’s next?
Join our mission to cure every rare disease on the planet, boldly venturing wherever the pursuit of revolutionary breakthroughs in biology may take us.
