All month, we are featuring stories of individuals who are having an impact in the fight against ALS.

Meet Dr. Tania Gendron, Assistant Professor of Neuroscience at the Mayo Clinic in Jacksonville, Fla. She fights ALS by working hard every day in the lab to find a cure for this devastating disease. Her work focuses on optimizing ALS biomarkers to track and better understand the most common genetic mutation in inherited ALS, called C9orf72.

The ALS Association has supported Dr. Gendron’s work as part of the TREAT ALSTM global research program with the hope to accelerate ALS biomarker progress. We are happy to report that she and her colleagues have made significant advances and recently published a paper in Annals of Neurology titled, “Phosphorylated neurofilament heavy chain: A biomarker of survival for C9orf72-associated amyotrophic lateral sclerosis.” Read more to learn how Tania contributes to ALS research by chipping away at the barriers between getting a drug from the lab and into clinical trials in her fight against ALS.

Q: Thank you for joining us today during August – about three years post the iconic ALS Ice Bucket Challenge! We are excited to learn more about your recent publication and your motivations to work in the lab every day for people living with ALS and their families. First, why do you love working in ALS research?

A: What I very much appreciate about working in ALS research is the great collaborative spirit within the field. Indeed, along with the instrumental efforts of Drs. Leonard Petrucelli and Kevin Boylan from the Mayo Clinic, my published study involved numerous investigators from around the world. Most important has been the keenness of ALS patients and caregivers to participate in such studies; our research is truly dependent on their contributions.

“I am extremely thankful to have received funding from The ALS Association and its donors to support my investigations on ALS biomarkers, as well as studies to elucidate the molecular mechanisms that cause ALS. It is my great hope that findings from my research will significantly contribute to the development of an effective treatment for ALS.” – Dr. Gendron

Q: What are the major findings on your paper? Congratulations on its publication!

A: Many potential treatments deemed promising in research laboratories have shown no therapeutic benefit upon testing in clinical trials. Among the various reasons for this is the lack of biomarkers to confirm that the drug being tested did in fact hit its intended target and to predict how quickly disease will progress. For example, one challenge in clinical trials is the fact that disease course can vary greatly among ALS patients, making it difficult to determine whether the drug being tested has an appreciable effect on survival.  Our study revealed that a phosphorylated form of neurofilament heavy chain (pNFH), which is a protein released from dying neurons, may help overcome this barrier. We found that pNFH levels are higher in the cerebrospinal fluid (CSF) of ALS patients compared to healthy individuals, and that there exists a strong relationship between levels of pNFH in ALS patients and how long they live after the onset of disease. Simply put, patients with low pNFH levels survive longer than patients with high levels. This was observed both in patients with sporadic ALS and patients with ALS caused by a repeat expansion in the C9orf72 gene (c9ALS). Of interest, we discovered that c9ALS patients have higher pNFH levels, more rapid disease progression and shorter survival than ALS patients without a C9orf72 expansion.

Q: What is the potential impact of these findings on the ALS field?

A: We hope that our findings will ultimately improve the design of clinical trials and thus their success. Although the clinical course of disease can vary substantially among ALS patients, the ability of the pNFH biomarker to predict survival would allow the stratification of patients into more uniform groups, such as to improve our ability to detect treatment outcomes.

Q: What are your next steps to continue this study?

A: Many clinical trials for neurodegenerative disorders are believed to have been hampered because treatment was initiated too late. Unfortunately, given that diagnostic delays occur, early treatment will not always be feasible. Thus, we will examine pNFH in CSF and blood collected over time from asymptomatic and symptomatic C9orf72 expansion carriers to determine at what point pNFH levels begin to rise in relation to symptom presentation. This is expected to inform when best to initiate treatment.

Q: Why did you and your colleagues decide to focus on the C9orf72 expansion mutation versus all the other identified inherited ALS genes?

A: First, because repeat expansions in C9orf72 are the most common known cause of ALS. Second, because knowing the genetic cause of this form of ALS gives us an advantage in deciphering how the mutation wreaks havoc in the central nervous system; this provides important insight into potential therapeutic targets. For instance, we know that the C9orf72 expansion leads to the accumulation of RNA molecules with a repeating sequence that set in motion a host of detrimental events within cells. Since this repeat RNA is believed to be toxic, therapeutics that target it are being pursued, such as antisense oligonucleotides (ASOs) that bind to the repeat RNA. As ASO therapy and other strategies make their way to clinical trials, we believe it is crucial to address barriers in moving a treatment from bench to bedside, such as the above-mentioned lack of biomarkers. We previously identified a biomarker to monitor target engagement of repeat RNA-based therapies for c9ALS. However, since forthcoming clinical trials will also benefit from biomarkers that predict disease course, we investigated pNFH biomarkers based on encouraging data from the ALS field.

Q: What do you enjoy doing outside the lab?

A: I love being outdoors but when the weather here in Jacksonville, Fla., gets unbearably hot, you’re more likely to find me engrossed in a good book.

We thank Dr. Gendron and the countless other ALS scientists out there tirelessly working together to end ALS for good.

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Read more about Dr. Gendron’s work here.

Paper citation:

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis.

Gendron TF; C9ORF72 Neurofilament Study Group, Daughrity LM, Heckman MG, Diehl NN, Wuu J, Miller TM, Pastor P, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Benatar M, Silani V, Glass JD, Floeter MK, Jeromin A, Boylan KB, Petrucelli L.

Ann Neurol. 2017 Jul;82(1):139-146. doi: 10.1002/ana.24980.

READ OPEN ACCESS ARTICLE HERE.