Phase 1 study shows encouraging data for gene replacement therapy for SMA type I

November 1, 2017, Nationwide Children's Hospital
Jerry Mendell, M.D. Credit: Nationwide Children's Hospital

A one-time intravenous infusion of the high dose of gene therapy extended the survival of patients with spinal muscular atrophy type 1 (SMA1) in a Phase 1 clinical trial, according to a study published today in the New England Journal of Medicine. The study was conducted by Researchers from Nationwide Children's Hospital in collaboration with AveXis, Inc. and The Ohio State University College of Medicine.

"My team at Nationwide Children's has worked with commitment and dedication to develop a that may subsequently be shown through future clinical trials to potentially alter the course of this unforgiving condition and provide a therapeutic option for the families and infants with SMA1," says Jerry Mendell, MD, principal investigator in the Center for Gene Therapy at Nationwide Children's.

SMA1 is a progressive, childhood, neuromuscular disease caused by a mutation in a single gene. Children with SMA1 fail to meet motor milestones and typically die or require permanent mechanical ventilation by 2 years of age. The phase 1 clinical trial is the first to test the functional replacement of the mutated gene responsible for SMA1.

A one-time intravenous injection of modified adeno-associated virus serotype 9 (AAV9) delivered the SMN gene to 15 patients. Three patients received a low dose, while 12 patients received a . In the Phase 1 trial, patients in the high dose group demonstrated improvement in motor function and they had a decreased need for supportive care compared to the natural history of the disease.

Specifically, at the end of the study period, all 15 patients appeared to have a favorable safety profile and to be generally well tolerated. Of the 12 patients treated with the high dose, 92 percent of patients have achieved head control, 75 percent of patients can roll over and 92 percent of patients can sit with assistance. Seventy-five percent of these patients are now sitting for 30 seconds or longer. Two patients can crawl, pull to stand and stand and walk independently.

Learn how a one-time intravenous infusion of the high dose of gene therapy extended the survival of patients with spinal muscular atrophy type 1 (SMA1) in a Phase 1 clinical trial. Credit: Nationwide Children's Hospital

According to natural history of the disease, patients require nutritional and respiratory support by 12 months of age, and are not able to swallow or speak effectively. Of the patients who received the high dose in study, 11 patients are able to speak, 11 patients are fed orally and seven do not require bi-level positive airway pressure as of the data cut-off (August 7, 2017).

"In this first phase of clinical trials, we have observed preliminary results that appear to be promising compared to the of SMA Type 1," says Dr. Mendell, also a faculty member at The Ohio State University College of Medicine.

This study builds on nearly three decades of foundational research led by teams at Nationwide Children's and Ohio State's Wexner Medical Center and exemplifies the strong basic science and clinical bonds between the two institutions. Arthur Burghes, PhD, of Ohio State created a ground-breaking SMA mouse model that remains the standard by which all therapies, including AVXS-101, are initially tested. Senior author of the study, Brian Kaspar, PhD, during his appointment at Nationwide Children's discovered that the AAV9 vector was capable of crossing the blood brain barrier when injected into the vascular system to deliver directly to motor neurons. The two laboratories then collaborated to show that scAAV9-SMN, when delivered to SMA mice shortly after birth, completely prevented their neuromuscular disorder. The laboratories also collaborated to successfully prove that reversing a protein deficiency through gene therapy is effective in improving and stabilizing SMA in a large animal model. "In neurological disease, it is rare to go from gene defect to therapy so directly, and the fact that this has happened here in one place is perhaps even rarer," said John Kissel, MD, chair of Neurology at Ohio State and director of the SMA Clinic at Nationwide Children's.

AveXis, Inc., a clinical-stage company developing treatments for suffering from rare and life-threatening neurological genetic diseases, announced in July 2016 that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the treatment based on preliminary clinical results from the trial of AVXS-101.

"At AveXis, we are enormously pleased to see that all children who received AVXS-101 are alive and free of permanent ventilatory support at 20 months of age and older - an age where, sadly, only eight percent of untreated children with SMA Type 1 are expected to survive without permanent breathing support," said Dr. Kaspar, now serving as Chief Scientific Officer at AveXis. "The New England Journal of Medicine publication marks an exciting milestone in the development of AVXS-101."

Explore further: Researchers seek biomarker to assess spinal muscular atrophy treatment

Related Stories

Researchers seek biomarker to assess spinal muscular atrophy treatment

June 19, 2017
Spinal muscular atrophy (SMA) is the leading genetic cause of death in infants, affecting 1 in 11,000 live births. As promising new therapies such as those directly targeting survivor motor neuron (SMN) are entering clinical ...

CAR-T immunotherapy now approved for certain adult lymphoma patients

October 20, 2017
The Food and Drug Administration (FDA) has approved a breakthrough cancer therapy known as CAR-T for use in adults with advanced lymphoma. The therapy uses a patient's own white blood cells, which are modified in a lab and re-trained ...

Combined therapy could repair and prevent damage in Duchenne muscular dystrophy

August 9, 2013
New research on two promising gene therapies suggests that combining them into one treatment not only repairs muscle damage caused by Duchenne muscular dystrophy, but also prevents future injury from the muscle-wasting disease. ...

Gene replacement therapy offers viable treatment option for fatal disease

May 5, 2016
Spinal muscular atrophy (SMA) is a disease that causes progressive degeneration in the nerve cells that control muscles, thereby causing muscle weakness and eventually death. SMA affects approximately 200,000 people in the ...

Microdystrophin restores muscle strength in Duchenne muscular dystrophy

July 25, 2017
Researchers from Genethon, the AFM-Telethon laboratory, Inserm (UMR) and the Royal Holloway University of London demonstrated the efficacy of an innovative gene therapy in the treatment of Duchenne muscular dystrophy. Indeed, ...

Ohio State researchers design a viral vector to treat a genetic form of blindness

November 2, 2011
Researchers at Ohio State University Medical Center and Nationwide Children's Hospital have developed a viral vector designed to deliver a gene into the eyes of people born with an inherited, progressive form of blindness ...

Recommended for you

Analytical tool predicts genes that can cause disease by producing altered proteins

July 19, 2018
Predicting genes that can cause disease due to the production of truncated or altered proteins that take on a new or different function, rather than those that lose their function, is now possible thanks to an international ...

Childhood stress leaves lasting mark on genes

July 18, 2018
Kids who experience severe stress are more likely to develop a host of physical and mental health problems by the time they reach adulthood, including anxiety, depression and mood disorders. But how does early life stress ...

Study shows DNA methylation related to liver disease among obese patients

July 18, 2018
DNA methylation is a molecular process that helps enable our bodies to repair themselves, fight infection, get rid of environmental toxins, and even to think. But sometimes this process goes awry.

Protein found to be key component in irregularly excited brain cells

July 17, 2018
In a new study in mice, researchers have identified a key protein involved in the irregular brain cell activity seen in autism spectrum disorders and epilepsy. The protein, p53, is well-known in cancer biology as a tumor ...

World's largest study on allergic rhinitis reveals new risk genes

July 17, 2018
An international team of scientists led by Helmholtz Zentrum München and University of Copenhagen has presented the largest study so far on allergic rhinitis in the journal Nature Genetics. The data of nearly 900,000 participants ...

New platform poised to be next generation of genetic medicines

July 16, 2018
A City of Hope scientist has discovered a gene-editing technology that could efficiently and accurately correct the genetic defects that underlie certain diseases, positioning the new tool as the basis for the next generation ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.