Focused ultrasound allows ERTs to reach the brain in Pompe mice
Lab findings set stage for work on using FUS to deliver therapies in humans
Written by |
In the first study of its kind, U.S. researchers showed that focused ultrasound (FUS) could be used to allow approved enzyme replacement therapies (ERTs) — which can not get past the brain’s protective barrier in humans — to enter the brain of a mouse model of Pompe disease.
Once in the animals’ brains, the approved ERTs effectively increased GAA enzyme levels and reduced glycogen accumulation, which is a hallmark sign of the rare genetic disease.
The scientists detailed the process: FUS delivered sound waves so that two specific brain regions would be accessible by opening the blood-brain barrier, known for short as the BBB. This semi-permeable layer of cells normally serves to protect the brain, but also prevents most molecules from reaching the central nervous system (CNS, comprising the brain and spinal cord) — including available ERTs for treating Pompe.
“These results provide a strong foundation for the clinical translation of FUS-mediated BBB opening as a strategy to enable CNS delivery of enzyme replacement therapies in Pompe disease,” the researchers wrote, adding that this strategy could help “to overcome the problem of delivering drugs to the brain.”
The study, “Focused ultrasound delivery of enzyme replacement therapy to the brain of Gaa−/− Pompe disease mice,” was published in the journal Molecular Genetics and Metabolism.
Pompe disease is caused by mutations that disrupt the production or function of acid alpha-glucosidase (GAA), an enzyme that breaks down glycogen, a complex sugar molecule. As a result, glycogen accumulates inside cells, particularly muscle and nerve cells, leading to disease symptoms.
No approved ERTs can cross blood-brain barrier in people
ERT is the standard Pompe treatment. It supplies patients with a working version of the GAA enzyme, helping clear excess glycogen from cells, thereby easing symptoms. However, none of the therapies approved to date can cross the blood-brain barrier, which means that they are ineffective for treating Pompe-related changes in the brain.
Now, a team led by scientists at Brigham and Women’s Hospital and Harvard Medical School in Boston investigated the use of FUS, a minimally invasive technology, to temporarily open the blood-brain barrier as a strategy to deliver two approved ERTs — Lumizyme (alglucosidase alfa) and Nexviazyme (avalglucosidase alfa) — to the brain. Both Lumizyme and Nexviazyme are sold by Sanofi, which funded the study.
The mice underwent four treatment sessions, every other week. Each session consisted of the administration of diphenhydramine to avoid a possible allergic reaction to ERT, the ultrasound technology, and intravenous, or into-the-vein, administration of ERT. Lumizyme was given at 20 and 40 mg/kg doses, while Nexviazyme was administered at 8, 20, and 40 mg/kg doses.
FUS targeted two brain regions, the cortex and striatum, known to be affected in Pompe. MRI scans, performed after the first and fourth treatment sessions, showed that FUS led to the opening of the blood-brain barrier in both brain regions, although the effect was stronger in the cortex.
[This] study represents the first demonstration that [focused ultrasound (FUS)] can deliver clinically approved [enzyme replacement therapies (ERTs)] to the [central nervous system] in a Pompe disease model. … [These results suggest that] FUS has potential to overcome a key limitation of current ERTs by enabling access to affected brain regions.
In mice receiving FUS and Lumizyme, particularly the 20 mg/kg dose, the results showed a significant reduction in glycogen accumulation in both the cortex and the striatum compared with animals that did not receive the ultrasound procedure. Consistent with the benefits of FUS and ERT, levels of the GAA enzyme increased significantly in the cortex and striatum across treatment doses, the researchers noted.
In mice treated with FUS and Nexviazyme, a second-generation or newer ERT, there was also a reduction in glycogen buildup at all doses tested.
Use of either Lumizyme and Nexviazyme, along with FUS, also reduced a prominent feature of Pompe, the formation of vacuoles that alter the structure of cells and tissues in Pompe and represent the accumulation of glycogen.
Results are a first in Pompe research
According to the researchers, this “study represents the first demonstration that FUS can deliver clinically approved [ERT] to the [central nervous system] in a Pompe disease model.” The findings suggest that “FUS has potential to overcome a key limitation of current ERTs by enabling access to affected brain regions.”
These are early days, the team stressed, which much research still needed before the strategy could even potentially be tested in humans.
“Further translational studies are needed to define optimal brain targets, assess functional outcomes, and evaluate the safety and efficacy of this approach in larger animal models,” the team concluded.
