The Promise of Gene Therapy in Neurological Disorders (Podcast)

Earlier this year, more than 30 years after the Human Genome Project began, scientists sequenced the complete human genome. The field continues to evolve rapidly.

“What we learned even four years ago is old school compared to what we know today in the field of genetics,” says Dennis Lal, PhD, MS, assistant professor and assistant staff in Cleveland Clinic’s Genomic Medicine Institute and Neurological Institute. “You will be able to better care for your patients with all this new knowledge that is available.”

In the latest episode of Cleveland Clinic’s Neuro Pathways podcast, Dr. Lal discusses advances in genomic research that show promise for targeted gene therapy for neurological disorders. He examines:

• What we know today about the genome
• The complication of heterogeneity (i.e., that one gene does not necessarily equal one disorder)
• The development of genetic risk scores for diseases ranging from Alzheimer’s to epilepsy
• The state of gene therapy for common versus rare neurological disorders
• Current research projects, including the new Cleveland Clinic Brain Study of neurodegenerative disorders

Click the podcast player above to listen to the episode now, or read on for a short edited excerpt. Check out more Neuro Pathways episodes at clevelandclinic.org/neuropodcast or wherever you get your podcasts.

Excerpt from the episode

Podcast host Glen Stevens, DO, PhD: So, the goal is to identify the right genes and the right patients that would fit the therapy correctly. Where are we in that?

Dr. Lal: This is quite interesting. When it comes to moving toward genetic or targeted therapy, there’s typically a game plan. The first part is identifying the “causal gene.” However, in the end, geneticists do not “identify” a gene since a gene cannot cause disease; what causes the disease is a pathogenic mutation, which leads to an abnormal version of the gene and a wrongly built protein. And then, typically, what people do is they try to match patients by molecular type of defect (mutation and gene). What genetics told us is that a single disease, such as stroke or Alzheimer’s, can be explained by many different genes. So there is more molecular heterogeneity, which also correlates with clinical heterogeneity.

Once it’s figured out which gene produces which subtype of the disease, then people also have clinical biomarkers like endpoints that can be used in a clinical trial. And then people try to develop therapies where you, for example, replace the gene using a virus, which brings a healthy version of the gene into the body, or you can increase or stabilize the amount of remaining healthy gene through other novel genetic therapies. And this is what people try now.

There are remarkable advances that have been made for 10 to 20 neurological disorders, for example. These are typically rare disorders. But the beautiful thing is that if you look back at the literature and conferences over the last months to two years, for many rare diseases there are already examples where people can try to cure the disease in mice. And they can do it in about 1 in 20 or 30 diseases.

The beauty of these genetic approaches is that the framework is the same, but you only exchange the gene that you want to target. Basically, the vehicle — the approach of how this medicine works — is similar and you can exchange it. It’s the same underlying premise of the mRNA vaccines that we use to immunize ourselves against the coronavirus…. The same underlying premise or idea is also behind the targeted therapies for neurological diseases.… So that makes many people very hopeful that this will translate to human success as well.