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Cross-Cutting Therapies in Brain Disease: Gene Therapy

Learn how gene therapy for diseases like amyotrophic lateral sclerosis (ALS) are transforming brain disease research and treatment.

The developing field of gene therapy holds promise for treating a wide range of brain diseases by targeting their underlying genetic causes. Emerging gene therapy research is already providing answers for some forms of amyotrophic lateral sclerosis (ALS) and has resulted in successful treatments for spinal muscular atrophy (SMA).

One of the leading researchers of ALS and other neurodegenerative diseases, Timothy Miller, MD, PhD, David Clayson Professor of Neurology at Washington University School of Medicine in St. Louis, joined us for a webinar exploring the topic of gene therapy for brain disease. During the webinar, Dr. Miller discussed the role of genetics research in creating innovative therapies, how these findings impact people living with brain disease, and what this means for the future of brain disease research.

Gene Therapy Advancements for ALS

For most of his career, Dr. Miller’s research has focused on treating ALS. This progressive neurodegenerative disease is caused by the death of motor neurons—cells in the brain and spinal cord—leading to issues with mobility, speech, swallowing, and breathing. The rate and severity with which ALS progresses varies, but most people live only three to five years after diagnosis. 

“Most ALS is not genetic, but approximately 10% is,” says Dr. Miller. Of all genetic ALS cases, 10-20% are caused by a mutation in a gene called SOD1. This is the gene Dr. Miller and his team have targeted for treatment.

“If you think about abnormal genes, there’s a change in the genetic code that leads to a change in the RNA, and that leads to the buildup of toxic protein [responsible for causing nerve cell death in ALS],” explains Dr. Miller. RNA is a substance in the body that translates the genetic instructions in our DNA into biological processes, like the production of various proteins.

Researchers are currently working with a therapy called antisense oligonucleotides (ASOs), which work at the level of RNA. “The RNA is targeted, and the antisense drugs are a bit like an eraser,” says Dr. Miller. “[They] lower the RNA, and by lowering the RNA that’s producing this toxic protein, you then eliminate the toxic protein.”

A Promising New ALS Drug

Dr. Miller’s most recent research has focused on the drug Qalsody (formerly called tofersen). Qalsody is thought to work by binding to SOD1 RNA and degrading it, resulting in a decline in proteins created by the SOD1 gene. Reducing this toxic protein slows the progression of ALS and even improves symptoms for some people.

To measure Qalsody’s effect, Dr. Miller and his team looked at neurofilaments (structural components of neurons). When cells are damaged, neurofilaments leak and can be found in the blood and the fluid surrounding the brain and spinal cord. “These are biomarkers of nerve injury,” says Dr. Miller. “So high levels or low levels of neurofilament are indicators of how rapid the disease progression will be.”

The studies on Qalsody show a significant reduction of neurofilament levels after 12 weeks. “This data [shows] a substantial slowing of the neurodegenerative disease process,” says Dr. Miller. He notes that it took a little longer for individuals to see an effect on their symptoms, but they did notice results after about a year.

Loss of muscle strength is common for people with ALS, so Dr. Miller and his team wanted to measure Qalsody’s impact on that particular symptom. They found that people taking the drug had their strength stabilize after about 28 weeks. Even more promising, about 27% of people experienced increased strength over the course of the study. Dr. Miller and his team were thrilled by these findings.

“Who has seen somebody with ALS get better? Our answer, at least at our institution, is zero,” Dr. Miller says. “It’s not that it never happens, but it’s incredibly rare—and here in this study, 27% of people [are] getting better.”

Side Effects and Treating Other Forms of ALS

Dr. Miller points out that in rare instances, Qalsody has side effects, including spinal cord inflammation, optic nerve swelling, and chemical meningitis. He encourages anyone with SOD1 ALS to discuss the risks and benefits of this treatment with their doctor. Overall, he says the drug was tolerated very well and is optimistic about its positive effect on treatment. 

“In my 30 years as an ALS physician, this is the first study where I’ve personally seen people stop progressing and some of them recover function,” says Dr. Miller.

While Qalsody has shown promising results, Dr. Miller notes that it can only help about 1-2% of all individuals with ALS. “I think the challenge to researchers around the globe is now to find the right drug for the rest of ALS [cases],” he says.

How ALS Research Impacts Other Brain Diseases

Perhaps the most exciting thing about the recent success of gene therapy for ALS is what it means for the treatment of other brain diseases

While the SOD1 gene was targeted for ALS, other defective genes can be targeted to treat different diseases with genetic causes or variants. “The same blueprint that we’ve outlined here can be used for a number of other genetic disorders,” says Dr. Miller. “This is a technique that’s broadly applicable, and I think this can be done for many different neurodegenerative diseases.”

As an example, Dr. Miller points to emerging studies around using gene therapy to treat Alzheimer’s disease. “We have data showing that an antisense oligonucleotide approach can lower the levels of one of the proteins associated with Alzheimer’s disease,” he says. 

Clearing out clumps of misfolded proteins in the brain has a significant impact on slowing the progression of Alzheimer’s disease, and researchers are investigating whether such a treatment may also be able to improve symptoms.

The Importance of Gene Therapy on Future Brain Disease Research

Only through additional research will we unlock the full therapeutic potential of gene therapy. Because brain diseases are interconnected, finding treatments and cures for one will lead to treatments and cures for many others. Each new discovery has a ripple effect, offering hope and life-changing solutions for the millions of people impacted by brain disease worldwide.

Dr. Miller is excited about the future of gene therapy and its enormous potential to improve lives. He shares a testimonial from an individual with ALS who has already benefited from this treatment as a reminder of why this research is so important: 

“On the one-year anniversary of my diagnosis, when I should have died, I instead kicked a football 47 yards. On the second-year anniversary, I drove a golf ball 275 yards. On the three-year anniversary, I hit a baseball pitched by my son off the center field fence, then hoisted him in the air. That’s joy made possible by science.”

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