Can Gene Therapy Treat Dominantly Inherited Disorders?

Can Gene Therapy Treat Dominantly Inherited Disorders? 1024 575 Abbie Miller
Colorful illustration of gene therapy in action

Recent applications of adeno-associated virus (AAV) mediated gene therapy have focused mainly on correcting recessively inherited diseases. But what about dominantly inherited disorders? It looks like AAV could be a delivery mechanism for treating those genetic disorders, too.

Most applications of AAV-mediated gene therapy research are in recessively inherited rare diseases. The affected individuals have two copies of the “bad” gene, and receiving a copy of the “good” gene enables the cell to function (more) normally.

For dominantly inherited disorders, the goal is not to replace a gene that’s missing. There’s one bad copy of a gene in the cell, and it usually overrides the function of the good gene copy, explains Scott Harper, PhD, principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s. “You want to eliminate the bad copy to allow the good copy to function normally.”

“Until about 12-15 years ago, we didn’t have good technologies to do that with gene therapy,” he says.

However, in 1998, Andrew Fire, PhD, and Craig Mello, PhD, published a study that described gene silencing by RNA interference in Nature. The work would later earn the two a Nobel Prize.

While Drs. Fire and Mello first described the phenomenon in the roundworm Caenorhabditis elegans, the cells of all complex organisms use RNA interference to regulate gene expression. Cells produce microRNAs, which are processed but do not code for proteins. They bind to other RNA in the cell and cause them to be degraded.

“We and a few others have been working on how to co-opt this natural system for our purposes,” says Dr. Harper. “We can take natural microRNAs, change the sequence, clone and package them in an AAV9 viral vector for delivery to a patient. And we can target any gene we want.”

In his case, Dr. Harper wants to target DUX4 (double homeobox 4), the gene responsible for facioscapulohumeral muscular dystrophy (FSHD), a dominantly inherited muscular dystrophy with a widely variable phenotype. FSHD typically manifests in the second decade of life and progresses from there. However, early onset is possible.

“FSHD is complicated because there isn’t a uniform presentation of disease in patients,” says Dr. Harper. “Some patients may only experience muscle weakness in a localized area, such as the bicep. Others may have profound muscle weakness that impacts the whole body.”

Dr. Harper and his colleagues have been working to test the safety and efficacy of delivering interfering RNA targeted to DUX4 in small animal preclinical studies. Their hope is to develop a treatment that could be delivered systemically or via intramuscular injection to effectively reduce DUX4 expression in patients with FSHD.

“This whole line of research is relatively new,” Dr. Harper says. “In 10 years the FSHD field has identified the genetic cause of FSHD, and we and others have developed the needed animal models for the disease and now we’re looking at a strategy to use gene therapy to treat it. It’s exciting to see how the science is moving forward, and how what we learn regarding FSHD can be applied to other dominantly inherited diseases.”


  1. Fire A, Xu SQ, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegansNature. 1998;391:806-811.
  2. Wallace LM, Saad NY, Pyne NK, Fowler AM, Eidahl JO, Domire JS, Griffin DA, Herman AC, Sahenk Z, Rodino-Klapac LR, Harper SQ. Pre-clinical safety and off-target studies to support translation of AAV-mediated RNAi therapy for FSHDMolecular Therapy – Methods & Clinical Development. 2018 Mar 16;8:212-130.

Image credits: Nationwide Children’s

About the author

Abbie (Roth) Miller, MWC, is a passionate communicator of science. As the manager, medical and science content, at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. Before coming to Nationwide Children’s, Abbie used her communication skills to engage audiences with a wide variety of science topics. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association.