1-time gene therapy cuts need for enzyme treatments for Pompe children
Youngsters in small study also growing, seeing better quality of life
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A single dose of GC301, a gene therapy candidate in the pipeline at Beijing Genecradle Therapeutics, reduced the need for regular enzyme replacement therapy (ERT) for children older than 1 year with infantile-onset Pompe disease (IOPD), new study data show.
For the children in the small study — now ages 1 to 6, but for whom symptoms of the genetic disease began in infancy — use of the gene therapy also helped them grow, develop, and experience a better quality of life, according to the researchers.
These findings add to preliminary evidence from an earlier study involving infants with IOPD, which demonstrated benefits with GC301 treatment among younger children. Youngsters in that study were shown to reach key milestones, such as walking on their own, within one year of receiving the gene therapy.
As in that earlier study, the experimental gene therapy was generally well tolerated, with most side effects among the children being mild to moderate, the scientists noted.
Altogether, these results suggest GC301 “as a promising therapeutic avenue for IOPD,” the researchers wrote.
The study, “AAV9-mediated GAA gene therapy following enzyme replacement therapy discontinuation in children with infantile-onset Pompe disease,” was published in the journal eClinicalMedicine by researchers in China.
In Pompe disease, mutations in the GAA gene disrupt the function or production of an enzyme called acid alpha-glucosidase (GAA). This causes glycogen, a complex sugar molecule that’s normally broken down by GAA, to build up in cells, particularly muscle cells. As a result, muscles become weaker over time. In the infantile-onset form of the disease, symptoms begin in early infancy.
Gene therapy works by supplying a working copy of the gene mutated in Pompe so the body can produce the GAA enzyme on its own. The new gene is usually delivered using a modified virus, engineered not to cause disease.
Testing use of gene therapy in children on enzyme treatments
GC301 packages an optimized version of the GAA gene inside a viral vector called adeno-associated virus 9 (AAV9). The optimized gene is designed to help the body produce more of the GAA enzyme.
In an earlier Phase 1 clinical study (NCT05567627, ChiCTR2200063229) involving four babies with Pompe, ages 2 to 5 months, GC301 improved movement and heart function in three infants. All had previously received at least one dose of ERT, which works by supplying the body with a version of the missing enzyme.
ERTs are the only approved treatments for Pompe that address the condition’s underlying cause. But once started, patients need to be on Pompe ERT for their entire lives, with treatments typically given every other week.
This new Phase 1/2 clinical study (ChiCTR2200065664), conducted at a hospital in Beijing, tested how safe GC301 is and how well it works in older children. The six participants — three boys and three girls, ranging in age from 12.5 months to 50.8 months, or slightly older than 4 years — had received ERT for a prolonged period of time. While all received the gene therapy, one child later left the clinical study after developing severe pneumonia and restarting standard ERT. Data from that child were still included.
Before gene therapy, the children stopped enzyme treatments for a short period. Each received prednisolone, a corticosteroid, to calm the immune response, followed by a single intravenous, or into-the-vein, infusion of GC301. Prednisolone was continued for some time after to help prevent the immune system from attacking the viral vector (AAV9).
All of the children had delayed growth and development despite receiving ERT. Many had difficulty breathing and moving, enlarged hearts, and poor quality of life, according to the researchers.
5 of 6 patients ERT-free for 1 year, data show
Over one year, GC301 was generally well tolerated, the data showed. The most common side effects were upper respiratory infections and temporary increases in blood fats. One child developed severe pneumonia, temporarily needed a ventilator to help with breathing, and restarted ERT, but later recovered and stopped ERT again.
Among the “key findings” of the study, per the researchers, were “sustained ERT- and ventilator-free survival in five of six patients for one year.”
Heart function remained stable throughout the study, the team noted. The heart’s pumping ability, measured by the left ventricular ejection fraction, stayed within the normal range, and the heart muscle did not change. Heart rhythm and breathing measurements remained stable, with no major changes in lung function.
All children continued to grow after gene therapy, gaining both weight and height, according to the researchers. However, most remained smaller than average for their age, which showed that growth delays were still present, even though steady gains continued. Two children showed improvements on a standardized measure of motor function, and three children reached important developmental milestones, such as crawling, standing, or walking independently.
[This study] provides the first clinical evidence that a single intravenous infusion of GC301 is feasible, safe, and can confer therapeutic benefits in children with IOPD … who had received prolonged prior ERT.
Quality of life, assessed with a questionnaire completed by patients or caregivers, gradually improved over the year, the researchers noted.
“This indicates a potential enhancement in disease-specific health-related quality of life from the patients’ or caregivers’ perspective,” the researchers wrote.
In the blood, the activity of the GAA enzyme increased sharply during the first two weeks after treatment, then decreased to a lower but stable level. Muscle biopsies from three children confirmed that the healthy gene had reached muscle cells and reduced glycogen buildup.
“These preliminary findings suggest that AAV9-mediated GAA gene therapy may reduce reliance on ERT,” the researchers concluded.
According to the team, the study, though small, “provides the first clinical evidence that a single intravenous infusion of GC301 is feasible, safe, and can confer therapeutic benefits in children with IOPD (median age 25.5 months) who had received prolonged prior ERT (median 19.5 months).”
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