Researchers at the Icahn School of Medicine at Mount Sinai say they have developed a novel platform to overcome one of the biggest challenges in brain disease treatment: getting macromolecule therapeutics to cross the blood-brain barrier (BBB). Their study, published today online in Nature Biotechnology, describes a new method that safely and effectively delivers large therapeutic molecules into the brain—a discovery that could pave the way for treating a range of neurological and psychiatric disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and various forms of addiction.
The blood-brain barrier is a natural defense mechanism that protects the brain from harmful substances circulating in the bloodstream. But this same mechanism has thwarted drug developers as it also blocks the pathway for many potentially life-saving drugs from reaching the central nervous system (CNS). For chronic diseases like ALS, Alzheimer’s, and other neurological diseases, this limitation has been a significant hurdle in developing effective treatments. The Mount Sinai team’s new approach, based on a blood-brain barrier-crossing conjugate (BCC) platform, could solve this issue by enabling large molecules such as proteins and oligonucleotides to cross the barrier and reach their target areas in the brain.
The platform takes advantage of a biological process known as γ-secretase-mediated transcytosis, which facilitates the transport of large molecules into the CNS. By linking antisense oligonucleotides to a compound called BCC10, the researchers demonstrated that these agents could be delivered efficiently through a simple intravenous injection. In mouse models and human brain tissue, the technique was shown to silence harmful genes associated with neurological disorders.
“The blood-brain barrier is an essential defense mechanism, but it also presents a significant challenge for delivering drugs to the brain,” said senior author Yizhou Dong, PhD, a professor of immunology and immunotherapy at Icahn Mount Sinai. “Our BCC platform breaks this barrier, allowing biomacromolecules, including oligonucleotides, to reach the CNS safely and efficiently.”
In their experiments, the investigators injected antisense oligonucleotides linked to BBC10 into mouse models and showed that that these conjugates successfully reduced the activity of genes involved in ALS and Alzheimer’s disease. In a transgenic mouse model of ALS, the BCC10 platform significantly lowered the expression of the gene Sod1, which causes motor neuron degeneration. Similarly, a different antisense oligonucleotide targeting the tau protein gene MAPT was shown to reduce its expression, a key step in the fight against Alzheimer’s.
“This development has the potential to advance treatments for a broad range of brain diseases,” said senior author Eric J. Nestler, MD, PhD, professor of neuroscience at Icahn Mount Sinai. “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.”
The platform also demonstrated a high degree of safety in mice, with minimal damage to major organs. The researchers now plan to extend their studies to larger animal models to further evaluate the therapeutic potential of the BCC system.
