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Barrow Clinical Trial Evaluating Gene Therapy for Familial ALS

Barrow Neurological Institute is one of 17 centers worldwide participating in a clinical trial that will evaluate a gene therapy for the inherited form of amyotrophic lateral sclerosis (ALS) caused by a mutation on the SOD1 gene.

“The SOD1 gene was the first gene that was identified and found to cause familial ALS,” said Neurologist and ALS Specialist Dr. Shafeeq Ladha, the site investigator for the trial and the director of the Gregory W. Fulton ALS and Neuromuscular Disease Center at Barrow.

The mutation is inherited in an autosomal dominant fashion, meaning a person can inherit the gene mutation from just one parent.

“If a parent has the disease, he or she usually has one bad copy and one good copy of the gene,” Dr. Ladha said. “So, there’s a 50/50 chance whether that person’s child will have the bad copy or the good copy.”

SOD1 normally provides instructions for making an enzyme called superoxide dismutase, which is abundant in cells throughout the body. This enzyme helps break down superoxide radicals, which are byproducts of normal cell processes but can damage cells if not broken down regularly.

Scientists believe mutations in SOD1 convert this normally helpful enzyme into a toxic protein that damages motor neurons and causes ALS. Motor neurons are the cells in the brain and spinal cord that send signals to muscles. When these nerve cells deteriorate and die, the brain can no longer initiate and control muscle movements. The muscles that control speaking, swallowing, and breathing are also eventually affected.

Shafeeq Ladha, MD
Neurologist and ALS Specialist

The drug in this study is from a class of drugs called antisense oligonucleotides (ASOs), which interfere with gene expression by altering RNA function. This particular ASO is given through a spinal injection and binds to the messenger RNA molecule created by the SOD1 gene. Messenger RNA, or mRNA, plays an important role in delivering messages from DNA to cells so that cells can produce the proteins that perform many essential functions in the body.

“If you have the SOD1 mutation, then you’re making an abnormal form of the messenger RNA,” Dr. Ladha explained. “This drug specifically interferes with the SOD1 messenger RNA and prevents it from producing the SOD1 protein, so you actually get reduced amounts of this toxic protein in the nervous system.”

The main objective of the Phase 1 study is to evaluate the safety and tolerability of the drug in people with ALS as well the drug’s pharmacokinetics—how it is absorbed, distributed, and metabolized by the body.

About 72 people will be enrolled and randomly selected to receive the drug or a placebo. The participants will be tested in groups, with the first group receiving the lowest dose a single time. If that appears to be safe, the following groups will be given higher one-time dosages. Investigators will then test multiple doses in people, again beginning with the lowest dosage and increasing the concentration if it appears to be safe.

According to the ALS Association, as many as 30,000 Americans are living with ALS at any given time. Familial ALS represents only about 10 percent of ALS cases, and known mutations in SOD1 account for only about 2 percent of all ALS cases.

However, Dr. Ladha discussed how ASO therapy could potentially have a greater impact.

The mechanism involved in this gene therapy could be applied to other gene mutations that have been linked to ALS, such as the C9orf72 mutation. [Related story: Barrow, IBM Watson Health ID New Genes Involved in ALS] This mutation has been linked to both familial and sporadic ALS cases. Sporadic ALS occurs in people with no family history of the disease.

“In fact, there is planning underway right now for a trial using this same kind of concept for the C9orf72 gene,” Dr. Ladha said.

By studying familial ALS, we learn a lot about the pathways that might be involved in sporadic ALS and then we can investigate those.

-Dr. Shafeeq Ladha, Barrow Neurologist and ALS Specialist

He also noted that the concept of introducing an ASO that interferes with how DNA and RNA are processed and read could be applicable to other diseases besides ALS, such as Huntington’s disease, spinocerebellar ataxia, and myotonic muscular dystrophy. The U.S. Food and Drug Administration has already approved drugs that use this mechanism to treat spinal muscular atrophy and Duchenne muscular dystrophy.

“You would essentially just design the ASO for the specific messenger RNA that you want to interfere with,” Dr. Ladha said.

He also explained that if gene therapy trials can help researchers gain a better understanding of how specific genes cause ALS, then researchers can learn a lot more about the factors involved in the death of motor neurons.

“By studying familial ALS, we learn a lot about the pathways that might be involved in sporadic ALS and then we can investigate those,” Dr. Ladha said. “I think it will really allow us to generate more ideas for therapy development in sporadic ALS.”

Find an ALS clinical trial at Barrow.

About Barrow

Since our doors opened as a regional specialty center in 1962, we have grown into one of the premier destinations in the world for neurology and neurosurgery. Our experienced, highly skilled, and comprehensive team of neurological specialists can provide you with a complete spectrum of care–from diagnosis through outpatient neurorehabilitation–under one roof. Barrow Neurological Institute: Discover. Educate. Heal.