Fetal Gene Therapy May Ease SMA Symptoms, Prolong Survival, Mouse Study Shows

Gene therapy administered while newborns are still in the womb may lessen spinal muscular atrophy (SMA) symptoms and prolong survival, a mouse study shows.

The study, “Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice,” was published in the journal Molecular Therapy.

SMA comprises a group of neurodegenerative disorders characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness and wasting. The disease is normally caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein that is essential for motor neuron survival.

Gene therapy is a relatively new approach that has been gaining popularity in clinical practice as a way to treat diseases caused by genetic mutations. It involves delivering a functional version of a gene to correct or replace a faulty gene within specific cells in the body.

To deliver the corrected version of the gene to cells, researchers use special viral vectors that work as “carriers.” Adeno-associated viruses, or AAVs, are one of the most used viral vectors in gene therapy due to their ability to infect and deliver the corrected gene to both dividing and non-dividing cells without causing any harm.

Gene therapy is already being used as a treatment for SMA. The 2019 approval of Zolgensma (onasemnogene abeparvovec-xioi), a gene therapy co-developed by AveXis and Novartis for the treatment of all types of SMA in newborns and toddlers up to the age of 2, was a landmark that highlighted the potential of AAV-based gene therapies to treat rare genetic disorders.

However, a new form of gene therapy, known as fetal gene therapy, is starting to gain attention as a possible option to treat genetic disorders that have an early onset, including SMA, Duchenne muscular dystrophy (DMD), and cystic fibrosis (CF). The idea behind fetal gene therapy is to deliver the corrected version of a gene before birth, as opposed to later in life.

“Fetal gene therapy offers the advantage of delivering therapeutic transgenes prior to disease onset and complete development of immune system, called ‘preimmunity,’ ” the researchers said, adding that “delivering of transgene into the stem cells provides longer gene expression and reduces the necessity for further re-administration.”

These researchers from Ege University in Turkey and their collaborators set out to investigate the efficacy of fetal gene therapy in a mouse model of SMA.

They used a construct (AAV9-SMN) to deliver a functional copy of the human SMN gene to 14- and 15-day-old mouse embryos, using the AAV9 viral vector.

They tested two different methods to deliver the AAV9-SMN construct to unborn mice: One involved injecting the construct into the mother’s placenta (intraplacental, or IP); while the other involved injecting the construct into the brain ventricles of the embryos (intracerebroventricular, or ICV). Ventricles are brain cavities that are filled with fluid.

After testing both methods, they found that delivering the construct through an ICV injection was more efficient, because a higher number of cells incorporated the construct, leading to its extensive expression across the animal’s central nervous system (consisting of the brain and spinal cord).

After establishing the delivery method that yielded better results, researchers treated mouse embryos with a single ICV injection of the AAV9-SMN construct and monitored their development after birth.

Their analyses showed that, depending on which type of cassette — an essential element of the construct that allows for the expression of the desired gene — was used to carry the human SMN gene, treated mice had a median survival of 63 or 105 days, living much longer than those that had not been treated (untreated SMA mice cannot survive more than 14 days). However, their lifespan was still shorter than that of healthy animals, which have a median lifespan of 405 days.

The team found a similar trend regarding the animals’ weight, with treated animals (3.5 g or 4.16 g) weighing more than those with SMA that had not been treated (2.61 g), but less than healthy animals (5.73 g).

Moreover, SMA mice that had been treated with fetal gene therapy had normal levels of the SMN protein in their brains and spinal cords, as well as a higher number of motor neurons, compared with untreated animals.

“For the first time, we demonstrated that fetal gene therapy using AAV9 could alleviate disease symptoms and increase the lifespan of treated SMA mice,” the researchers wrote.

“It is time to consider the benefits and move forward with fetal gene therapy to reveal its true potential for patient benefits,” they said. However, “before fetal gene therapy can be allowed to reach its full potential in the clinical setting, other issues … need to be addressed, ranging from ethical to cultural and protocols provided. However, time is of the essence.”