In this episode, we’ll dig into the different mechanisms by which gene therapy can potentially treat specific genetic diseases – such as amyotrophic lateral sclerosis, or ALS, and others.
And they did it, in part, by examining the genealogy of a particular family in Vermont. In 1835, a farmer named Erastus Farr died of a mysterious illness characterized by a progressive weakening of his muscles followed by paralysis and respiratory failure.
Thirty years later, his descendent Samuel Farr died of the same condition, as did four of Samuel’s eight children, the youngest at the age of 27.
By 1880, the Canadian physician Sir William Osler had studied the Farr family phenomenon and concluded that they all suffered from a newly identified disease known as amyotrophic lateral sclerosis.
But how could this frightening condition be passed from one generation to the next?
Over the next hundred years, scientific interest in the disease grew, especially after the legendary baseball player Lou Gehrig died of the disease in 1941.
But there was still a mystery: while 90% of ALS cases are considered sporadic – meaning there is no hereditary connection – the other 10% of cases seemed to run in families, like the Farrs. After the dawn of the genetic age, scientists began to suspect a gene variation was at the heart of the mystery. And then finally, in 1993, scientists including Robert Brown at the University of Massachusetts medical school, who studied the Farr family and others while also investigating the human genome, uncovered the answer.
In some ALS patients, a variant of a single gene, called SOD1, can cause a buildup of toxic proteins in the brain, leading to the various symptoms that characterize the disease. In this case, the goal of gene therapy is to block or silence the abnormal production of a protein.
And solving that mystery has paved the way for gene therapy, perhaps someday soon, to provide the first known treatment for familial ALS.
For more education on gene therapy, visit www.genetherapynetwork.com.
DDx SEASON 4, EPISODE 5
ALS, DMD and Adapting Treatment Mechanisms for Genetic Variations
RAJ: This season of DDx is brought to you by Novartis Gene Therapies.
KIM: In 1993, a multinational group of scientists and doctors solved a medical mystery 150 years in the making.1,2
And they did it, in part, by examining the genealogy of a particular family in the town of Sutton, Vermont, just a few miles from the Canadian border.2,3 In 1835, a farmer named Erastus Farr died of a mysterious illness characterized by a progressive weakening of his muscles followed by paralysis and respiratory failure.2,3
Thirty years later, his descendent Samuel Farr died of the same condition, as did four of Samuel’s eight children, the youngest at the age of 27.4
By 1880, the Canadian physician Sir William Osler had studied the Farr family phenomenon and concluded that they all suffered from a newly identified disease known as amyotrophic lateral sclerosis, or ALS.2
But how could this frightening condition be passed from one generation to the next?
Over the next hundred years, scientific interest in ALS grew, especially after the legendary baseball player Lou Gehrig died of the disease in 1941.5
But there was still a mystery: while 90% of ALS cases are considered sporadic—meaning there is no hereditary connection—the other 10% of cases seemed to run in families,2,6 like the Farrs of Vermont.3
Fast forward to the 1990s, scientists began to suspect a gene variation was at the heart of the ALS mystery. And then finally, in 1993, scientists including Robert Brown at the University of Massachusetts medical school, who studied the Farr family and others while also investigating the human genome, uncovered the answer.2,7
In some ALS patients, a variant of a single gene, called SOD1, can cause a buildup of toxic proteins in the brain, leading to the various symptoms that characterize the disease.8,9
And solving that mystery has paved the way for gene therapy, perhaps even leading to treatment for familial ALS.
RAJ: This is DDx, a podcast from Figure 1 about how doctors think.
I’m Dr. Raj Bhardwaj.
This season I’m joined by co-host Kim Handysides as we take a deep dive into gene therapy.
Today we’re talking about the different mechanisms by which gene therapy can potentially treat specific genetic diseases.
KIM: Before we talk more about SOD1 and the next chapter of the ALS story, there are a few important things to know about the different ways in which gene therapy works.
There are numerous ways in which genetic variations occur and have the potential to cause disease, but two of the most common types of variation are gene deletion and gene hyperfunctioning.10 And so, to address these two different types of disease mechanisms, scientists developing gene therapies must come up with a specific mechanism for each type.9
Let’s start by talking about gene deletion – we’ll get to gene hyperfunctioning in a minute.
Gene deletion occurs when the DNA sequence for a particular gene is absent.11 This usually contributes to a particular protein deficiency, which is at the core of the disease. The goal of gene therapy here is to develop and deliver a replacement gene to restore the protein function and treat the underlying disease.9,12
A great example of this mechanism is with a disease called Duchenne muscular dystrophy, or DMD.13
Like ALS, DMD was first described by scientists in the 19th century—in this case, by a French neurologist named Guillaume Duchenne. But it wasn’t until the late 1980s when researchers isolated the genetic root of the disease—the absence of a protein they called dystrophin.14
Most of us possess a dystrophin-producing gene (called DMD gene) located on the X-chromosome, and it encodes this critical protein, which regulates muscle growth and protects against damage.14,15
But about six out of every 100,000 people lack the ability to produce this protein because some sequence of the gene is absent from their DNA.14
The signs of Duchenne muscular dystrophy can appear in children as young as two, with abnormal muscle development hindering physical abilities like walking and jumping.14
There is commonly progressive muscle degeneration and weakness in both the extremities and the axial muscles of the body.14
And ultimately there can be acute respiratory failure14—all because the body can’t produce this one protein.
Today, scientists are developing a gene therapy that could deliver a lab-altered gene into the cells of a human host to effectively jumpstart the production of dystrophin and, if treatment starts early enough, potentially cut off the disease’s development trajectory.13
The replacement gene, in other words, would correct the genetic flaw. And this is at the heart of emerging gene therapy treatments not only for Duchenne but also spinal muscular atrophy (SMA) and a host of other genetic diseases.12
Like Duchenne, SMA is caused by a gene deletion, in this case called survival motor neuron gene (SMN1), that leads to a deficiency of a protein with the same name. The result of SMN protein deficiency is the death of motor neurons in the spinal cord.12,16 SMA has a similar course to Duchenne muscular dystrophy, it could lead to death from respiratory failure.12
Scientists have learned how to replace missing or damaged genes into cells in different tissues, such as muscle and central nervous system. These can produce dystrophin or other missing proteins.8,12
We talk more about these amazing gene delivery tools, known as viral vectors, in other episodes. The replacement gene is loaded into a viral vector and delivered to the host cell, going to lodge in the nucleus, from where the new gene will be responsible for the production of proteins like dystrophin.8,12,17
KIM: But when it comes to familial ALS, the type of genetic variation is different, and so the mechanism of a gene therapy must be adapted to that difference.9
Unlike diseases like Duchenne where the protein-building gene is absent, with ALS, the gene is still present—it’s just hyperfunctioning, or overactive. And as a result, the body is not lacking a particular protein but instead producing excessive amounts of it—often with toxic results. In this case, the goal of gene therapy is not to replace a missing protein but instead to block or silence the abnormal production of a protein.8,9
After that pivotal moment in 1993 when scientists identified the SOD1-gene as the root of familial ALS disease, research accelerated to determine what was actually happening in some nerve cells of these patients.18
SOD1 (Superoxide Dismutase 1) refers to an enzyme gene located on chromosome 21, that plays a role in motor neurons, leading to normal muscle function, much like dystrophin.19
And what subsequent studies have demonstrated is that these variant SOD1 genes carry an erroneous blueprint for the construction of that protein. The protein is misfolded, and as a result it becomes hyperfunctioning.8,20
The mutated SOD1 protein becomes toxic, and this damages other proteins in the motor neurons and leads to the terrifying symptoms of ALS.20
These damaged neurons are now becoming the target for a different kind of gene therapy—a gene silencer. The goal is to slow or even reverse the toxic aggregation of proteins by turning off that hyperfunctioning SOD1 gene.9,18
About 20 percent of familial ALS patients and 1-2% of sporadic ALS patients have a hyperfunctioning SOD1 gene,8 and in the future gene therapy has the potential to possibly save these lives.7
Meanwhile, over the last 30 years, scientists have discovered other genes besides SOD1 whose hyperfunctioning may lead to ALS—including mutations in C9orf72, TARDBP, and FUS.⁸ For each of these variations, a specific gene therapy will need to be developed to silence the hyperfunction and reverse the protein buildup.⁸ It’s a fascinating field with many challenges yet ahead, but the progress in gene therapy research is encouraging.
RAJ: Special thanks to Dr. Rodrigo Mendonça – a neurologist who works with neuromuscular disorders – for sharing his expertise in the research of this episode.
This is DDx, a podcast by Figure 1.
Figure 1 is an app that lets doctors share clinical images and knowledge about difficult to diagnose cases.
I’m Dr. Raj Bhardwaj, co-host and story editor of DDx.
You can follow me on Twitter at Raj BhardwajMD.
Head over to figure one dot com slash ddx, where you can find full show notes, photos and speaker bios.
This episode was brought to you by Novartis Gene Therapies.
For more education on gene therapy, visit gene therapy network dot com.
Thanks for listening.
- SOD1 (copper zinc superoxide dismutase 1) and ALS. ALS Association. Accessed November 24, 2021. https://www.alsa.org/research/focus-areas/genetics/sod1.html
- Siddique T, Ajroud-Driss S. Familial amyotrophic lateral sclerosis, a historical perspective. Acta Myol. 2011;30(2):117-120.
- Albright C. Book Chronicles How A Vermont Family Stricken With ALS Keeps Hope Alive. Vermont Public Radio. Published December 1, 2015. Accessed November 24, 2021. https://www.vpr.org/vpr-news/2015-12-01/book-chronicles-how-a-vermont-family-stricken-with-als-keeps-hope-alive
- Allen AW. Family Ties ALS Patient to Illness–and Healing. Los Angeles Times. Published July 4, 1999. Accessed November 24, 2021. https://www.latimes.com/archives/la-xpm-1999-jul-04-mn-52900-story.html
- Waldstein D. As M.L.B. Honors Lou Gehrig, It Shines a Spotlight on A.L.S. The New York Times. Updated June 3, 2021. Accessed November 26, 2021. https://www.nytimes.com/2021/06/01/sports/baseball/lou-gehrig-day.html
- Genetics. ALS Association. Accessed November 24, 2021. https://www.als.org/research/research-we-fund/scientific-focus-areas/genetics
- Dr. Brown vs ALS. UMass ALS Cellucci Fund at UMass Chan Medical School. Accessed November 25, 2021. https://www.umassmed.edu/umass-als-cellucci-fund/dr-brown-vs-als/
- Amado DA, Davidson BL. Gene therapy for ALS: A review [published online ahead of print, 2021 Apr 9]. Mol Ther. 2021;S1525-0016(21)00195-7.
- Gene Therapy. ALS News Today. Published April 22, 2019. Accessed November 26, 2021. https://alsnewstoday.com/gene-therapy/
- How can gene variants affect health and development? MedlinePlus Genetics. Accessed November 26, 2021. https://medlineplus.gov/genetics/understanding/mutationsanddisorders/mutationscausedisease/
- Deletion. National Human Genome Research Institute. Accessed November 26, 2021. https://www.genome.gov/genetics-glossary/Deletion
- Abreu NJ, Waldrop MA. Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy. Pediatr Pulmonol. 2021;56(4):710-720.
- Promising gene therapy for Duchenne muscular dystrophy. UC Davis Health. Published April 28, 2021. Accessed November 25, 2021. https://health.ucdavis.edu/health-news/newsroom/promising-gene-therapy-for-duchenne-muscular-dystrophy/2021/04
- Duchenne Muscular Dystrophy (DMD). Muscular Dystrophy Association. Accessed November 24, 2021. https://www.mda.org/disease/duchenne-muscular-dystrophy
- Duchenne muscular dystrophy. Genetic and Rare Diseases Information Center (GARD). Accessed November 24, 2021. https://rarediseases.info.nih.gov/diseases/6291/duchenne-muscular-dystrophy
- Spinal Muscular Atrophy Fact Sheet. National Institute of Neurological Disorders and Stroke. Accessed November 25, 2021. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Spinal-Muscular-Atrophy-Fact-Sheet
- How does gene therapy work? MedlinePlus Genetics. Accessed November 25, 2021. https://medlineplus.gov/genetics/understanding/therapy/procedures/
- Fessenden J. Silencing of an ALS gene safely delivered to patients in UMass Medical School study. UMass Med News – UMass Chan Medical School. Published July 8, 2020. Accessed November 25, 2021. https://www.umassmed.edu/news/news-archives/2020/07/silencing-of-an-als-gene-safely-delivered-to-patients-in-umass-medical-school-study/
- Genetics of ALS. ALS Association. Accessed November 25, 2021. https://web.alsa.org/site/PageServer?pagename=ALSA_Genetics_ALS
- Fellman M. Protein in Lou Gehrig’s Disease Linked to Neuron Death. Northwestern Medicine. Published November 1, 2005. Accessed November 25, 2021. https://news.feinberg.northwestern.edu/2005/11/als/