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New AAV approach allows gene therapies to cross the blood-brain barrier

Written by Aaron Khemchandani, Science Writer.

A new study, published in the journal Nature Biomedical Engineering, has shown how delivery vehicles can be tweaked to enable gene therapies to cross the blood-brain barrier. This novel approach could aid the treatment of brain cancers, potentially revolutionizing how scientists use vectors to transport selected genes.

The blood-brain-barrier: friend and foe

The blood-brain barrier (BBB) poses significant challenges for gene therapy. Formed of tightly wedged rows of cells, the BBB prevents any toxins or pathogens that may be present in the blood from entering brain tissue. The downside is it also keeps out potential treatments for central nervous system (CNS) diseases.

Specific delivery vectors – known as adeno-associated viruses (AAVs) – can cross the barrier in certain circumstances, but most of the time AAVs are inefficient at delivering gene therapies to the brain. Now, researchers at Brigham and Women’s Hospital have unveiled a novel AAV variant that (when tested in preclinical models) was markedly more efficient than previous delivery vehicles.

“Our study is exciting because it shows that we are one step closer to being able to deliver gene therapy across the blood-brain barrier in humans,” explained Fengfeng Bei, PhD, Department of Neurosurgery, Brigham and Women’s Hospital. “Our findings demonstrate that AAVs could provide a valuable tool for developing systemic gene therapies against glioblastoma and other diseases where CNS delivery is required.”

Overcoming long-standing challenges

So how did the team develop their novel AAV approach? AAVs are non-disease causing viruses that can be engineered to carry and deliver specific genes into target cells. Recent biotechnological progress combined with preclinical successes in AAV-mediated gene silencing, editing and replacement has painted this type of vector in a positive light, elevating overall optimism for the future of gene therapy.

However, most AAVs identified to date are not considered efficient enough for use in clinical settings. To overcome this seemingly stubborn hurdle, Bei and his colleagues turned to cell-penetrating peptides – a group of short peptides known to be able to cross biological membranes like the BBB.

The team collected approximately 100 of these peptides and inserted them into a variety of AAVs. They then tested each AAV variant in the hope that at least one of them would display improvements in gene delivery – and it worked. “We got lucky,” Bei said. “We got a hit right around number 16”. That is, the AAV.CPP.16 variant showed significant enhancements in delivery efficiency across the BBB relative to previously tested variants.

Where do we go from here?

Despite this hugely promising success, Bei’s team is looking to go even further in their research. “We’d like to develop a version that is even more efficient and more restricted to the central nervous system,” he said. “Our studies to date tell us we’re headed in the right direction.”

These findings suggest that the newly-identified vector could be used to treat genetic diseases in which turning on protein production in a specified number of cells could reverse or improve prognoses. “New treatments are urgently needed for neurometabolic diseases, lysosomal storage diseases and other diseases that affect both CNS tissue and other tissues in the body,” said Yulia Grishchuk, PhD, who leads a lab in the Center for Genomic Medicine at Massachusetts General Hospital and recently collaborated with Bei’s team. “What is exciting here is that this work could represent a way to treat a broad spectrum of CNS disorders that are hard to target with current treatment approaches.”

More on these topics

Brain / CNS / Gene Therapy / Genetics / Genomics