Valentine’s Day for people with multiple sclerosis: promoting brain repair through remyelination
Current disease-modifying therapies in multiple sclerosis are all focused on suppressing the inflammatory phase of the disease. This has been extremely successful, and it is doubtful that significantly more efficacious anti-inflammatory treatments will be found. However, it remains the case that people with relapsing-remitting multiple sclerosis acquire disability on treatment, and enter the secondary progressive phase. I argue that we now need treatments that prevent neuronal degeneration. The most promising approach is to prevent axons degenerating by remyelination. Since the discovery that the adult brain contains stem cells which can remyelinate, the problem now is how to promote endogenous remyelination, and how to know when we have achieved this! We have successfully identified one drug which promotes remyelination but unfortunately it is too toxic for use in the clinic. So the hunt continues.
The pathophysiology of prodromal Parkinson’s disease
Studying the pathophysiology of late stage Parkinson’s disease (PD) – after the patients have experienced severe neuronal loss – has helped develop various symptomatic treatments for PD (e.g., deep brain stimulation). However, it has been of limited use in developing neuroprotective disease-modifying therapies (DMTs), because DMTs require interventions at much earlier stages of PD when vulnerable neurons are still intact. Because PD patients exhibit various non-motor prodromal symptoms (ie, symptoms that predate diagnosis), understanding the pathophysiology underlying these symptom could lead to earlier diagnosis and intervention. In my talk, I will present a recently elucidated example of how PD pathologies alter the channel biophysics of intact vagal motoneurons (known to be selectively vulnerable in PD) to drive dysautonomia that is reminiscent of prodromal PD. I will discuss how elucidating the pathophysiology of prodromal symptoms can lead to earlier diagnosis through the development of physiological biomarkers for PD.
Genetic therapies for Huntington’s disease, what does the future hold for neurodegenerative disorders?
There are no effective disease-modifying therapies for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis or Huntington’s disease. Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease and the world’s most common genetic dementia. I will present an overview of important approaches in development for targeting mutant HTT DNA and RNA (Tabrizi et al Neuron 2019), the cause of HD pathogenesis, and the translational pathway from bench to clinic for a HTT targeting antisense oligonucleotide (Tabrizi et al New England Journal of Medicine 2019, Tabrizi, Science 2020) which is now in phase 3 studies. In my talk I will also review some of the genetic approaches in development for other CNS diseases. I will talk a bit about my journey as a clinician scientist and share some of my learnings for young scientists on how to survive a career in science.