What is Protein Misfolding?
DNA is the foundational code for all proteins. The linear information in DNA is first “decoded” into linear strands of amino acids. These strands must then fold in a very precise, highly complex way to form proteins with distinct shapes and functions. When this folding goes awry, critical functions are lost and, even worse, renegade proteins can set off cascades of destruction, causing brain cells to malfunction and die. This was one of the earliest biological problems solved by life on earth and the mechanisms are shared from yeast to man.
Protein misfolding plays a key role in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). For each of the diseases, as the “culprit proteins” misfold, they damage nerve cells in various ways. The cellular stresses caused by protein misfolding lead to aggregation, or clumping of proteins, which form sticky deposits in the brain cells themselves or in brain tissue, resulting in nerve cell damage and, ultimately, cell death. Because this is an ancient problem, these proteins damage yeast cells in similar ways, allowing unprecedented high-throughput screening for correcting compounds. Current research and drug discovery efforts have been stymied by a lack of adequate tools to study the protein folding defects that are at the heart of these diseases and discover new drugs that will correct them.
Yumanity Therapeutics’ Integrated Discovery Platforms
Yumanity Therapeutics’ new approach to neurodegenerative disease drug discovery and development concentrates on correcting the cellular pathologies driven by misfolded proteins, the altered biology or phenotypes. The company’s proprietary platforms have already identified one potential new target for treating Parkinson’s disease, and Yumanity Therapeutics is actively advancing its new chemical lead series for this condition, as well as identifying additional compounds for Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). Yumanity’s unique approach overcomes the fundamental limitations of the most commonly used strategies in drug discovery today, which have repeatedly failed to deliver effective therapies for these diseases.
Yumanity Therapeutics’ three integrated platforms enable the company to move back and forth between yeast cells and human patient neurons in a highly iterative and parallel fashion, continually building on lessons learned with multiple protein pathologies in order to accelerate the discovery of novel therapies. These discovery platforms are comprised of:
- Several proprietary ultra high-throughput, phenotypic screening (uHTS) platforms, in which different protein misfolding pathologies are modeled in yeast to help discover compounds to correct these pathologies;
- A human neuronal platform, in which neurons produced from the stem cells of patients with disease-causing genetic mutations are used to validate the molecules discovered in yeast; and,
- A drug-target identification platform that exploits the power of yeast genetics and protein network analyses to elucidate mechanisms of action for pathology correcting molecules as new chemical entities are discovered.
Yumanity Therapeutics’ three integrated platforms were developed over the years by a team of young scientists in the Lindquist laboratory and were transformed into a robust drug discovery engine by the company’s scientific co-founders, Drs. Vikram Khurana, Chee Yeun Chung and Daniel Tardiff. Drs. Khurana, Chung and Tardiff helped pioneer the integration of yeast and human neuronal systems, coupling genetic and protein-network analyses with yeast ultra-high-throughput screening to accelerate the identification of promising new drug candidates and their molecular targets. The three integrated platforms have been described in multiple peer-reviewed publications.
Addressing Critical Need in Neurodegenerative Diseases
Diseases affecting the brain and central nervous system represent one of the largest global healthcare challenges and greatest medical needs due to the devastating personal and economic consequences for patients, caregivers and society. It is estimated that more than 55 million people worldwide suffer from neurodegenerative diseases, with no currently approved disease-modifying therapies available.1,2,3 As modern therapeutic interventions increase life expectancy, the number of patients suffering from these diseases is expected to double every 20 years.1,2 Global costs for treating these diseases are currently estimated at $818 billion and expected to grow to more than $1 trillion by 2030.1,2,3
Yumanity Therapeutics is advancing a new strategy in targeting the underlying protein pathology of neurodegenerative diseases, which allows the company to discover therapies that may modify the root cause of these neurodegenerative diseases rather than only addressing their symptoms. The company’s is currently focused on Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), with future applications across multiple additional protein misfolding diseases.
1. UBS, Alzheimer’s Report, July 2014; Industry Research
2. Alzheimer’s Disease International, World Alzheimer Report 2015
3. Parkinson’s Disease Foundation. http://www.pdf.prg/en/parkinson_statistics