Promising mouse study lays foundation for first gene therapy trial in SMARD1
Treatment shown to improve survival in model of this rare SMA type
Written by |
- SMARD1 is a rare form of spinal muscular atrophy that causes severe motor impairment and respiratory issues.
- In a preclinical study, a gene therapy was shown to extend survival and improve motor function in SMARD1 mouse models.
- The treatment is now being tested in people with SMARD1 in a clinical trial.
Treatment with gene therapy significantly prolonged survival and improved motor function in a mouse model of spinal muscular atrophy with respiratory distress type 1 (SMARD1), researchers report.
The gene therapy tested in this lab study is now being evaluated in a small U.S. clinical trial (NCT05152823) involving children with SMARD1-causing gene mutations. That study is enrolling by invitation at Nationwide Children’s Hospital in Columbus, Ohio.
“Our present study supported lead candidate selection for [preclinical safety] studies that ultimately lead to the initiation of the first in human clinical trial for treatment of SMARD1,” the researchers wrote.
Titled “AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model,” the study was published in the Journal of Biomedical Science.
SMARD1 is a rare type of spinal muscular atrophy (SMA), caused by mutations in the IGHMBP2 gene. Like the more common forms of SMA, which are caused by mutations in another gene called SMN1, SMARD1 is marked by the death and degeneration of motor neurons — the nerve cells that control movement.
While there is a lot of variability among patients, SMARD1 is usually a severe disease that causes marked motor impairment and difficulty breathing. Most children with SMARD1 die in infancy, and there are no available treatments proven to slow SMARD1 progression in people.
Gene therapy aims to address disease’s root genetic cause
The basic aim of gene therapy for diseases such as SMA and SMARD1 is to deliver a healthy version of the defective gene to cells, addressing the root genetic cause of the disease.
For people with SMA, two gene therapies have been approved in the U.S.: Zolgensma (onasemnogene abeparvovec-xioi), authorized for patients younger than 2, and Itvisma (onasemnogene abeparvovec-brve), which was recently approved for people with SMA ages 2 and older. These gene therapies have been proven to at least slow disease progression for people with the common forms of SMA.
To deliver a healthy version of the SMN1 gene to motor neurons, both Zolgensma and Itvisma use the same gene therapy construct: a modified version of adeno-associated virus serotype 9 (AAV9). This virus has emerged as a useful tool for gene therapies because it’s good at getting genes into human cells, but it typically doesn’t cause illness in people.
Because SMA and SMARD1 are both genetic diseases that affect motor neurons, and AAV9-based gene therapy has proven effective for children with SMA, scientists reasoned that this approach might also be effective for people with the rarer SMARD1.
A research team in Italy and the U.S. created two AAV9-based gene therapy candidates designed to deliver a healthy version of the IGHMBP2 gene to motor neurons, then tested them in a mouse model of SMARD1.
Both treatment candidates tested in this study used the same AAV9-based vector. The key difference between them was the promoter that they used. A promoter is basically a genetic sequence that acts as a molecular switch, as it’s where a gene starts being read — sort of like putting a capital letter at the start of a sentence. One of the therapy candidates used a promoter called CBA; the other used a promoter called P546, which has been used with success in early studies using animal models of Rett syndrome, another rare genetic disorder.
Here, the researchers found that both gene therapy candidates significantly prolonged lifespan. Specifically, most untreated SMARD1 mice died before one month of age, whereas most mice given either gene therapy lived to four months or longer. Measures of motor function also showed significant improvements in mice given either of the gene therapies. Gains to levels similar to control mice were also seen in body weight for as long as 200 days of testing.
“Both vectors lead to a highly significant extension of survival and amelioration of the motor phenotype [changes] if compared to the empty vector (null) [control without gene therapy], confirming the efficacy of gene therapy in the SMARD1 mice,” the researchers wrote.
Both therapies tested showed benefits for SMARD1
The team noted that both therapies preserved the number of motor neurons in the spinal cord and improved nerve supply at the neuromuscular junction, where is where nerves and muscles communicate.
“Overall, we demonstrated that gene therapy is able to improve the two main pathological [disease-related] hallmarks of motor neuron diseases,” the team wrote.
Further benefits included attenuation of astrogliosis, which occurs when cells called astrocytes respond to damage in the central nervous system (brain and spinal cord), and of microglial activation. This a key process in neuroinflammation that is initially protective but can lead to degeneration if it’s long lasting.
Additional experiments showed that the candidate using the P546 promoter led to better long-term preservation of motor neurons and of the neuromuscular junction. Given those findings, it was selected for further development. It also reduced a heart defect marked by excessive scarring relative to the CBA promoter.
The ongoing Phase 1/2 trial is using a gene therapy based on the P546 candidate.
