A new way to cross the blood–brain barrier

Researchers at the Icahn School of Medicine at Mount Sinai have developed an innovative approach to deliver therapeutics into the brain, creating a blood–brain barrier-crossing conjugate (BCC) system designed to overcome the protective barrier that typically blocks large biomolecules from reaching the central nervous system (CNS). Their breakthrough, which has been published as a study in the journal Nature Biotechnology, provides new possibilities for treating a wide range of neurological and psychiatric diseases.

The blood–brain barrier is a natural protective shield that prevents harmful substances from entering the brain; however, it also blocks the delivery of life-saving drugs, creating a significant challenge in treating conditions like amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, addiction and many other CNS disorders. As noted by Professor Yizhou Dong, co-corresponding senior author on the study, “The blood–brain barrier is an essential defence mechanism, but it also presents a significant challenge for delivering drugs to the brain.”

The BCC platform has been designed to break this barrier by taking advantage of a specialised biological process called γ-secretase-mediated transcytosis to deliver large therapeutic molecules, like oligonucleotides and proteins, directly into the brain through a simple intravenous injection. This allows these biomacromolecules to reach the CNS safely and efficiently, addressing a pressing need.

The study showed that when the researchers injected a compound called BCC10 linked to specialised genetic tools known as antisense oligonucleotides into mice, it successfully reduced the activity of harmful genes in the brain. In a transgenic mouse model of ALS, the treatment significantly lowered levels of the disease-causing gene called Sod1 and its associated protein. Similarly, a different antisense oligonucleotide linked to BCC10 greatly reduced another gene, Mapt, which encodes the tau protein and is a target for the treatment of Alzheimer’s disease and other dementias.

BCC10 proved to be highly effective at delivering these genetic tools to the brain, improving their ability to silence harmful genes in different models and even in samples of excised human brain tissue studied in the laboratory. Importantly, the treatment was well tolerated in mice, causing little or no damage to major organs at the tested doses, the investigators said.

“Our platform could potentially solve one of the biggest hurdles in brain research — getting large therapeutic molecules past the blood–brain barrier safely and efficiently,” said co-corresponding senior author Professor Eric J Nestler, Chief Scientific Officer of the Mount Sinai Health System. “This development has the potential to advance treatments for a broad range of brain diseases.”

Next, the investigators plan to conduct further studies in large animal models to validate the platform and develop its therapeutic potential.

Image credit: iStock.com/Ihor Lukianenko