Written by Dr. Hannah Shorrock
Edited by Dr. Hayley McLoughlin
Early involvement of patients in clinical trial design, developing innovative imaging techniques and leveraging a clear understanding of disease mechanisms will pave the way for clinical trial success in the ataxias.
As the field of ataxia research moves towards clinical trials, it is important to establish a clear path forward. The keynote talk by Dr Nina Schor from the National Institutes of Health set the stage for the future of ataxia clinical trials by highlighting the need for multinational collaborations between academic, clinical, and industry scientists with government agencies, advocacy groups, and early involvement of patients. Each of these groups brings a very different set of values and expertise to the discussion on clinical trial design ensuring that clinical trials meet the needs of all parties involved. The keynote provided food for thought for the rest of the conference with many of the points being reiterated or exemplified in the plenary talks, breakout sessions, and workshops.
“Why, when, and how [to] involve patients? The answer is Yes!” - Dr Nina Schor
The importance of involving patients early in clinical trial design was greatly stressed by the keynote speaker. It was highlighted that the outcome measures of a clinical trial, the measurements that decide whether a treatment is successful in preventing or reversing disease progression, should be relevant to patients and their families. In other words, outcome measures should have a meaningful impact on patients’ lives. This speaks to the point that it is hard to determine if something is successful when the baseline is not static. This must be understood and addressed up front in the clinical trial design process, something that would be greatly facilitated by all relevant parties being involved at the inception of a trial and ensuring that patients are heard in this process.
The many different groups that should be involved in clinical trial design all bring different knowledge and values to the discussion. Some will be critical in promoting, supporting, and organizing the necessary multinational platform for ataxia trials. With rare diseases, there is a small number of patients in any one country, and inclusion criteria normally further reduce that number. This results in the need for patients from across multiple countries to be able to reliably detect changes in outcome measures. Multinational trials will also ensure equity to access trials and will enable the trials to account for genetic and environmental diversity in response to treatments or outcome measures. Other parties will be essential for designing and implementing innovative trial formats. Innovative trial designs will be key to assessing different therapeutics in small patient populations and will help to understand if the treatments have real-world impacts on patients. Finally, the keynote speaker also highlighted the need to recruit and train the best and brightest to join the ataxia research team by thinking creatively to get those with the potential to contribute to join the fight against ataxia.
“There are only so many times you can drop a screw before the drill goes through the window” – Patient Panelist Quote
Following the keynote session, there was a panel discussion by ataxia patients. The goals of this session were to educate ICAR attendees on three different topics based on the patient’s experiences:
- convey how symptoms impact the quality of life
- explain how symptoms are managed
- describe successful ways that researchers and patients can interact
This session was especially important for those who normally do not have interactions with patients or are new to ataxia research. Learning about daily life and the frustrations that can accompany seemingly simple tasks, such as those involved in home renovation, was highly educational for basic science researchers. When researchers present ‘background’ information to the scientific community, we commonly talk about the clinical symptoms and expect the scientific audience to infer how that would impact day-to-day living. But we frequently say nothing of the frustrations that the clinical symptoms might cause. We do not describe how those symptoms are managed outside of the clinical context and we do not say how important mindset is in the personal fight against ataxia. As one patient said: “you’re not supposed to get better. I’ll take that bet and try.” Being educated on the diseases that we research helps scientists to improve their knowledge, improve how we communicate about these diseases to the wider scientific community, and provide inspiration and context for why the research we conduct is so important.
Understanding disease mechanisms provides novel targets for therapies
Why do different populations of neurons degenerate? Why is degeneration age-dependent? How are the disease-causing genes regulated? These were some of the key questions addressed in the first session on disease mechanisms in ataxias.
Researchers from across the globe have been busy addressing these questions and presenting research on their findings at ICAR. Attendees learned that there are age-related and disease-specific changes in gene expression across different regions of the cerebellum of SCA2 mice. In SCA6 mice, there is an initial compensation for neuron dysfunction that becomes compromised as the mice age. This may contribute to the age-dependent degeneration seen in SCA6. Using a new mouse model of ARSACs, researchers identified that there is a failure of electrical signals to travel along Purkinje neuron axons which occurs in a cell-dependent manner. Researchers also identified that in ARSACs, the mutant sacsin protein is degraded as it is being made resulting in loss of the protein. Together this research starts to address some of these questions and enables researchers to move towards thinking about how to correct these molecular alterations.
Identifying factors that govern regional or age-dependent degeneration and factors that regulate the expression or processing of the disease-causing genes will help to identify novel targets for therapies. This was exemplified by talks on SCA1, Friedreich’s Ataxia, ATXN2, and SCA3. In SCA1, researchers identified that therapeutically targeting deleterious effects of glial cells on Purkinje neurons improved the health and function of both the glia and neurons. In Friedreich’s Ataxia, removing the repeat expansion using gene editing corrected defects in how the FXN RNA is made and processed. Researchers discussed that reduction in ATXN2 levels leads to improvement in different models of neurogenerative diseases possibly because knocking down levels of ATXN2 prevents cell death caused by damage to DNA. Finally, it was shown that targeting a regulator of ATXN3 levels in a zebrafish model of SCA3 can lead to a reduction of ATXN3 protein levels and improve motor function. Together these presentations provided clear examples of how understanding the mechanisms of disease is key in identifying new therapeutic targets across different types of ataxias.
The importance of consistent training and clinical understanding
In the Tuesday afternoon session, conference attendees had the opportunity to participate in a clinical grand rounds session and attend a workshop on neuroimaging techniques.
Workshops such as this provide a platform for a consistent approach to be discussed and best practices taught to new researchers in the field. In the case of neuroimaging, something that will be utilized in clinical trials, having a consistent approach across different sites is essential to ensure the reproducibility and accuracy of results. Indeed, one of the key goals of the session was to ensure attendees had appropriate knowledge to facilitate decision-making in clinical trial design. Similarly, there were discussions on the use of different acquisition approaches and MRI outcome measures for understanding neuroimaging in diagnosis, clinical trials, and for the understanding of the disease.
Many basic academic and industry scientists will not commonly see the clinical side of ataxia research and diagnosis. The grand rounds sessions at the conference provide academic and industry scientists with clinical perspectives that are often hard to come by for non-clinical scientists. Clinicians presented case studies covering family history, symptoms, and clinical tests, and then other clinicians would suggest possible diagnoses before the official diagnoses and genetic test results were revealed. This session provided insight into the clinical complexities faced by clinicians and a platform for clinicians to discuss the diagnosis of newly identified ataxia subtypes with genetic causes. Like the patient panel session earlier in the day, for the non-clinical scientists, this provided an insight into the experiences of patients throughout the diagnosis process, which was often lengthy or occurred many years after symptom onset.
A multinational focus for moving ataxia research forward
Throughout the Tuesday afternoon session at ICAR, the need for a multinational focus for moving ataxia research forward was highlighted. Researchers from across the globe congregated at ICAR to present their research, establish collaborations, and network with peers. Making these international connections facilitates sharing of knowledge, resources, funding opportunities, and links with advocacy groups, government agencies, and patients that will be essential for establishing the multinational networks through which successful clinical trials will be conducted.
About the Author and Editor
Hannah Shorrock is a postdoctoral researcher at the RNA Institute, University at Albany, studying small molecule therapeutic approaches for spinocerebellar ataxias caused by CAG repeat expansions. She has no conflict of interest to declare regarding this session.
Dr. Hayley McLoughlin is an Assistant Professor in the University of Michigan Neurology Department, with a joint appointment in the Department of Human Genetics. Her lab currently focuses on establishing pathogenic mechanisms and therapeutic interventions for SCA3. She has no conflict of interest to declare regarding this session.
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