Claudio Hetz, a professor in the Faculty of Medicine at the University of Chile, was awarded an MDA research grant totaling $294,000 over a period of three years to study a potential new therapy aimed at rescuing motor neurons in amyotrophic lateral sclerosis (ALS). In ALS, some proteins do not fold into their required shape correctly, triggering stress-response pathways which can be detrimental to neurons. Hetz aims to use a gene therapy approach to target one of these stress response pathways, known as the “Unfolded Protein Response” (UPR). If successful, the work could point the way to a new therapeutic target at which to aim treatments for this fatal disease.

Please describe your current research.

We are committed to the study of cellular strategies involved in adaptation to chronicendoplasmic reticulum (ER) stress. The ER has important cellular functions, highlighting its role as sophisticated machinery for protein folding and secretion. ER stress engages an integrated signaling pathway known as the “Unfolded Protein Response” (UPR), which aims to restore homeostasis. Nevertheless, the mechanisms that control the transition from an adaptive state to cell death processes remain unknown and are a central subject of our research. We are currently developing a systematic approach to underscore the effects of targeting the UPR in ALS using genetic manipulation of the pathway in mouse models in addition to developing gene therapy strategies to alleviate ER stress.

What inspired you to study ALS?

Most people do not think that neurodegenerative diseases can be cured. The poor quality of life of patients and the burden of health care on family members and society fuel our challenge to find therapeutic approaches to treat this terrible disease. From a scientific standpoint, ALS can be considered a proteinopathy, which provides us much of the inspiration to develop new therapeutic ideas based on cellular mechanisms linking protein homeostasis and neurodegeneration. The development of ALS models has opened an exciting avenue for preclinical studies. By establishing an extensive collaborative network with experts in different fields, we are confident that our basic and translational research will have a positive impact on patient care in the long-term.

What is your area of focus within the ALS field and why is it important?

We focus on basic pathogenic mechanisms and genetic and pharmacological approaches to attenuate ER stress levels by modulating the unfolding protein response in preclinical models of ALS.

We and several other labs have obtained extraordinary results showing that ER stress is the earliest event observed in the disease that may trigger the degeneration cascade. ER stress is a transversal event in familial and sporadic forms of the disease. Thus, we believe that strategies to target ER stress levels may have tremendous implications for disease treatment.

Why is it important that MDA continue to fund research in ALS?

I think that we are making substantial progress towards a possible treatment for ALS. The outcome of large unbiased studies from patient samples to animal models of the disease pointed towards ER stress as a key feature of ALS, reinforcing its value as therapeutic target. Given the transversal aspect of ER stress in ALS, we anticipate that familial or sporadic cases will benefit from therapeutic approaches developed using our strategy.

What do you feel people impacted by ALS can have the most hope about with respect to research right now?

Patients affected with ALS now need to know that we are working for them, even though our current scientific efforts will benefit next generations. They can have the hope that we are doing our best effort to contribute to finding a possible cure for this disease, and that families suffering from loss of beloved ones and uncertainty about their future will count on powerful treatments to live a normal life. We feel completely motivated and convinced to dedicate our careers to fight ALS.

Does your work have any potential implications for other disease fields?

Absolutely. Most neurodegenerative diseases also involve ER stress. More mechanistic studies on how ER stress participates at early stages of these diseases/conditions are needed at this point.