In the latest episode of The Genetics Podcast, Patrick spoke with Dr. John Lepore, physician-scientist and CEO of ProFound Therapeutics. ProFound Therapeutics, a company incubated at Flagship Pioneering, is leading an entirely new approach to drug discovery by exploring the "expanded human proteome." With a background spanning nearly two decades at GSK, where he ultimately led R&D as Senior Vice President, Dr. Lepore brings deep experience in translating scientific discoveries into impactful therapeutics.
In this episode, Dr. Lepore shares how his team is uncovering previously unknown proteins that could lay the foundations for entirely new medicines. He also talks about the role of human genetics in their discoveries and how ProFound Therapeutics is finding the balance between research and developing real-world treatments.
From physician-scientist to drug discovery leader
Dr. Lepore began his career as a physician, but his curiosity about the underlying causes of disease pulled him toward research. During his postdoctoral training and later at the University of Pennsylvania, he focused on understanding the genetic drivers of cardiovascular development and disease, bridging the gap between clinical practice and scientific discovery.
It was at GSK, however, where he truly found his passion for drug discovery. Over his 17-year tenure, he worked across multiple therapeutic areas, leading teams focused on metabolic, cardiovascular, and immunological diseases, and playing a key role in GSK’s genetics-driven drug discovery efforts. While he thrived in the large pharma environment, he was drawn to the opportunity at ProFound Therapeutics because of its vision: the possibility of discovering entirely new classes of proteins that could be drug targets or therapeutics themselves.
The expanded human proteome
Traditional drug discovery has largely been limited to the proteins encoded by the 20,000 genes identified in the Human Genome Project. However, Dr. Lepore and his team at ProFound Therapeutics are challenging this assumption. Using advanced ribosome profiling (Ribo-Seq) techniques, they are identifying thousands of novel proteins that were previously unknown. These proteins originate from open reading frames (ORFs) that had been overlooked due to constraints in early genomic annotation methods.
Some of these newly discovered proteins are smaller than traditional proteins, while others originate from alternative start codons. Despite being missed in earlier genomic studies, they are biologically active, dynamically regulated, and could represent an untapped reservoir of new drug targets.
ProFound Therapeutics is systematically mapping these proteins in what they call the "ProFoundry Atlas," a vast database integrating ribosome profiling, mass spectrometry, transcriptomics, and human genetic data. By layering this data with information from large-scale genetic studies, they can identify which of these proteins are functionally important in disease and therefore prime candidates for drug development.
Using human genetics to identify novel drug targets
One of the most exciting parts of ProFound Therapeutics’ work is its potential to find new genetically validated drug targets. Many genome-wide association studies (GWAS) have identified disease-linked genetic variants that do not map to known protein-coding genes. Some of these so-called “non-coding” variants may actually be impacting the expression or function of these newly discovered proteins.
By linking genetic variants to previously unknown proteins, the team at ProFound Therapeutics is not only helping us to better understand the biological mechanisms of disease but also identifying potential intervention points for novel therapeutics. This approach allows them to develop drugs with a higher likelihood of success, as genetically validated targets have historically been more successful in clinical trials.
Building a therapeutic pipeline
While the expanded proteome opens up a number of scientific possibilities, ProFound Therapeutics is focused on turning these discoveries into real-world treatments. Dr. Lepore stresses that they’re not just identifying new proteins, they’re actively building a pipeline of potential medicines.
One of their biggest priorities is oncology. By pinpointing proteins that are highly expressed in tumors but absent in healthy tissue, they’re developing new targets for cutting-edge cancer therapies. And beyond cancer, they’re also exploring how their genetic insights could lead to breakthrough treatments in metabolic and immune-related diseases.
In collaboration with Pfizer and Pioneering Medicines, ProFound Therapeutics is also investigating how these newly discovered proteins might play a role in obesity and metabolic disease. This partnership reflects their broader strategy, working with pharma companies to fast-track drug development and ensure their discoveries have the greatest possible impact on patients.
The challenges and opportunities of novel target discovery
Discovering and targeting novel proteins is an exciting yet complex challenge. Unlike working with well-characterized proteins, developing treatments against previously unknown targets requires additional validation and mechanistic understanding. However, Dr. Lepore sees this challenge as an opportunity: by focusing on targets that have strong genetic validation and clear biological relevance, they aim to de-risk their programs early in development.
To streamline progress, ProFound Therapeutics is focusing on established therapeutic modalities, such as monoclonal antibodies and recombinant proteins, rather than introducing additional complexity with newer drug technologies. This strategy allows them to concentrate on validating the biology of their targets while leveraging proven drug development approaches to move forward efficiently.
Looking ahead
ProFound Therapeutics is redefining what’s possible in drug discovery by expanding our understanding of the proteome. Looking ahead, they plan to move their lead programs toward clinical trials, strengthen partnerships with pharmaceutical companies, and deepen their insights into this newly uncovered landscape of proteins. As proteomics continues to evolve, their work has the potential to change how we discover and develop new medicines, bringing hope to patients with conditions that currently have few or no treatment options.
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