What You Need to Know About Ferroptosis

Our research efforts at PTC are focused on two scientific platforms – splicing and ferroptosis and inflammation – where PTC has unique expertise to discover and advance innovative therapies to the clinic.

We recently sat down with Jeff Trimmer, Senior VP, Research Site Head, to learn more about ferroptosis, how it relates to inflammation and the team at PTC working on this program.

What does ferroptosis mean? 

Jeff: Ferroptosis is a recently discovered form of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. It is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis.

How would you describe it to a family member or a neighbor?

Jeff: Ferroptosis is a form of regulated cell death meant to protect biological systems from oxidative damage that in certain disease conditions becomes dysregulated and causes unwanted cell death.

Imagine the lipids that are essential for the structural integrity of cell membranes begin to rust (become oxidized) and lose their ability to protect the intracellular environment, causing the cells to die.

How does this relate to inflammation?

Jeff: The process of ferroptosis causes certain cell types that participate in the innate and adaptive immune response to become activated and produce pro-inflammatory cytokines.

Are they the same or different?

Jeff: Inflammation results from numerous stimuli, and ferroptosis is one of those.

Why have we grouped ferroptosis and inflammation together? 

Jeff: We have grouped them because a hallmark of ferroptosis that is understood to cause cell death and disease progression is inflammation.

Is there a specific type of inflammation we’re targeting? 

Jeff: Several of our current programs are targeting neuroinflammation—a critical aspect of disease pathology in neurodegenerative diseases such as ALS. Specifically, our compounds are designed to prevent activation of pro-inflammatory glial cells and astrocytes.

How does this differ from splicing? 

Jeff: We are targeting the activity of enzymes and biological pathways that are known to regulate ferroptosis versus targeting gene expression (post transcriptional control via the spliceosome).

What investigational treatments are in clinical development that originated from  this platform? 

Jeff: Vatiquinone (PTC743) and utreloxastat (PTC857) are development-stage products that were discovered using the ferroptosis and inflammation platform.

Where is the research for this platform conducted at PTC?

Jeff: Much of the work is performed in Mountain View, California; however, the development of new therapies would not be possible without the significant contributions of  our Pharmacology, DMPK and Chemistry colleagues in New Jersey.

What is your background and what’s interesting to you about this approach? 

Jeff: My graduate work focused on human metabolism, with an emphasis on understanding how metabolic processes adapt to environmental stresses, including diet, altitude and exercise. This steered me towards working on metabolic diseases such as type 2 diabetes when I joined the pharma industry.  I’m excited about my current work as it has provided an opportunity to learn about new disease indications such as ALS and Parkinson’s disease and contribute to developing a therapeutic approach to treating those diseases that has not been attempted previously. PTC is a clear leader in the field–on the cutting edge of understanding the role of ferroptosis in neurodegenerative disease.

Can you describe our team working on this platform? 

Jeff: We have assembled a very talented multi-disciplinary team of scientists and drug developers. This includes neuroscientists, chemists, enzymologists, pharmacologists and bioanalytical scientists. We all share the excitement of working on truly novel approaches to delivering medicines for diseases with a significant unmet medical need that are devastating for patients and their loved ones.