The blood-brain barrier (BBB) is an imposing enemy for gene therapy. Formed by cells packed tightly together, the BBB prevents toxins and pathogens that may be present in the blood from entering brain tissue, but it also prevents the potential treatment of diseases that affect the central nervous system (CNS). ). Researchers have discovered certain delivery vehicles – known as adeno-associated viruses (AAVs) – that can cross the barrier under certain circumstances, but most of the time AAVs are ineffective at transporting gene therapies. Researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, are working to optimize AAVs as gene delivery vehicles, improve their efficacy and potential to deliver drugs to treat brain cancers such as glioblastoma and genetic diseases that affect the central nervous system. In an article published in Nature Biomedical Engineeringthe research team reports on a new AAV variant tested in preclinical models that is significantly more efficient than previously developed delivery vehicles.
“Our study is exciting because it shows that we are on the verge of being able to deliver gene therapy across the blood-brain barrier in humans,” said Fengfeng Bei, PhD, of Brigham’s Department of Neurosurgery. “Our findings demonstrate that AAVs might provide a valuable tool for developing systemic gene therapies for glioblastoma and other diseases where CNS delivery is required.”
AAVs are small, non-pathogenic viruses that can be engineered to transport and deliver DNA sequences to targeted cells. Previous studies have shown them to be safe delivery vehicles for gene therapy, which aims to directly modify genes in cells to treat disease.
Recent advances have led to the discovery of a new generation of AAVs that can penetrate the BBB in mouse models, but most AAVs identified to date are not effective enough to be considered for use in the clinical setting. . To improve on existing AAVs, 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 around 100 of these peptides and inserted them into a variety of AAVs and tested them one by one to find the most effective.
“We were lucky,” Bei said. “We had a hit right around number 16.”
The team tested their discovery in preclinical models, examining both mice and non-human primates. While the AAV they identified – lucky number AAV.CPP.16 – showed significantly improved delivery efficiency across the blood-brain barrier compared to previously tested AAVs, the Bei’s lab is looking to make further improvements.
“We would like to develop an even more efficient version that is more restricted to the central nervous system. Our studies to date tell us that we are heading in the right direction,” he said.
These data suggest that the new vector might be used to treat genetic diseases in which activating protein production in a specified number of cells might reverse a disease. Yulia Grishchuk, PhD, who directs a lab at the Center for Genomic Medicine at Massachusetts General Hospital, recently collaborated with Bei and sees potential disease applications for her research team’s lab advancements.
“New treatments are urgently needed for neurometabolic diseases, lysosomal storage diseases and other diseases that affect both CNS tissues and other body tissues,” Grishchuk said. “What’s exciting here is that this work might represent a way to treat a wide range of CNS disorders that are difficult to target with current treatment approaches.”
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