Novel vector delivers genes across the blood–brain barrier
Researchers have developed a novel gene therapy that exploits the human transferrin receptor to successfully cross the blood–brain barrier.
Gene therapy delivered by adeno-associated virus (AAV) represents a promising avenue for the treatment of neurological disorders with a genetic basis. However, crossing the blood–brain barrier (BBB) is notoriously challenging, making it difficult to achieve effective concentrations of therapeutics in the brain.
To facilitate a more efficient transfer of gene therapies to the brain, researchers from the Broad Institute of MIT and Harvard (MA, USA) sought to target the human transferrin receptor – a well-categorized BBB transport protein already utilized by some brain-targeting antibody therapeutics. The team screened vast libraries of pre-existing engineered AAVs in search of those that could bind to the human transferrin receptor and identified a potential candidate called BI-hTFR1.
The group then injected BI-hTFR1 into the bloodstream of mice that expressed the human transferrin receptor to test whether it would cross the BBB. These mice displayed significantly higher levels of BI-hTFR1 in the brain and spinal cord compared with control mice, who did not have the humanized receptor – evidence that the human transferrin receptor was key in transporting the vectors across the BBB and into the nervous system.
Breakthrough in gene therapy for genetic deafness
Results from the ongoing Phase I/II CHORD trial for the investigational gene therapy DB-OTO have detailed improvements in the hearing of two children, both born with genetic deafness.
The group also compared BI-hTFR1’s transport efficacy with that of AAV9, a vector that is employed in an FDA-approved gene therapy for spinal muscular atrophy in pediatric patients but has seen low success in delivering therapeutic genes to adult brain cells. Concentrations of BI-hTFR1 in the humanized mice’s brain tissue were up to 50 times greater than those achieved by AAV9, reaching up to 71% of neurons in some regions of the brain. Additionally, the novel vector delivered 30 times as many healthy copies of GBA1 – a gene implicit in the development of several neurological disorders – than AAV9.
“Since we came to the Broad we’ve been focused on the mission of enabling gene therapies for the central nervous system,” explained Ben Deverman, director of the research group. “If this AAV does what we think it will in humans based on our mouse studies, it will be so much more effective than current options.”
Ken Chan, first co-author and leader in Deverman’s lab group, added, “These AAVs have the potential to change a lot of patients’ lives.”
The team hopes these novel AAV vectors will be easily scalable, paving the way for the treatment of a range of neurological disorders.
