Scientists Crack the Blood-Brain Barrier, Paving Way for New Alzheimer’s Treatments
A brand new system developed by Icahn Mount Sinai researchers allows the protected supply of therapeutic biomolecules to the mind by overcoming the blood-brain barrier. Tested in mouse fashions, it exhibits promise for treating neurological illnesses like ALS and Alzheimer’s.
Scientists at the Icahn School of Medicine at Mount Sinai have pioneered a groundbreaking methodology, examined in mouse fashions and remoted human mind tissue, to soundly and successfully ship therapies to the mind. This breakthrough opens up new avenues for addressing a wide range of neurological and psychiatric issues.
Published in Nature Biotechnology, the research introduces a first-of-its-kind blood-brain barrier-crossing conjugate (BCC) system, designed to beat the protecting barrier that sometimes blocks giant biomolecules from reaching the central nervous system (CNS).
The blood-brain barrier is a pure protecting defend that forestalls dangerous substances from getting into the mind. However, it additionally blocks the supply of life-saving medicine, creating a major problem in treating circumstances like amyotrophic lateral sclerosis (ALS), Alzheimer’s illness, dependancy, and lots of different CNS issues.
The BCC platform takes benefit of a specialised organic course of referred to as γ-secretase-mediated transcytosis to ship giant therapeutic molecules, like oligonucleotides and proteins, straight into the mind by means of a easy intravenous injection.
“The blood-brain barrier is an essential defense mechanism, but it also presents a significant challenge for delivering drugs to the brain,” says co-corresponding senior writer Yizhou Dong, PhD, Professor of Immunology and Immunotherapy, and a member of the Icahn Genomics Institute and the Marc and Jennifer Lipschultz Precision Immunology Institute, at Icahn Mount Sinai. “Our BCC platform breaks this barrier, allowing biomacromolecules, including oligonucleotides, to reach the CNS safely and efficiently.”
Promising Results in Preclinical Models
The research confirmed that when the researchers injected a compound referred to as BCC10 linked to specialised genetic instruments referred to as antisense oligonucleotides into mice, it efficiently decreased the exercise of dangerous genes in the mind.
In a transgenic mouse mannequin of ALS (a motor neuron illness), the remedy considerably lowered ranges of the disease-causing gene referred to as Sod1 and its related protein. Similarly, a distinct antisense oligonucleotide linked to BCC10 tremendously decreased one other gene, Mapt, which encodes the tau protein and is a goal for the remedy of Alzheimer’s illness and different dementias.
BCC10 proved to be extremely efficient at delivering these genetic instruments to the mind, bettering their means to silence dangerous genes in numerous fashions and even in samples of excised human mind tissue studied in the laboratory. Importantly, the remedy was nicely tolerated in mice, inflicting little or no injury to main organs at the examined doses, say the investigators.
Broad Potential for Brain Disease Treatments
Despite latest progress in the discipline, there’s nonetheless a urgent want for applied sciences that may bypass the blood-brain barrier and enhance the supply of biomacromolecule-based therapies to the central nervous system by way of systemic administration.
“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,” says co-corresponding senior writer Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic Affairs of Icahn Mount Sinai, and 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 additional research in giant animal fashions to validate the platform and develop its therapeutic potential.
The paper is titled “Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.”
Reference: “Intravenous administration of blood–brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system” by Chang Wang, Siyu Wang, Yonger Xue, Yichen Zhong, Haoyuan Li, Xucheng Hou, Diana D. Kang, Zhengwei Liu, Meng Tian, Leiming Wang, Dinglingge Cao, Yang Yu, Jayce Liu, Xiaolin Cheng, Tamara Markovic, Alice Hashemi, Brian H. Kopell, Alexander W. Charney, Eric J. Nestler and Yizhou Dong, 25 November 2024, Nature Biotechnology.
DOI: 10.1038/s41587-024-02487-7
The remaining authors, all with Icahn Mount Sinai besides the place indicated, are Chang Wang, MD; Siyu Wang, PhD; Yonger Xue, PhD; Yichen Zhong, BS (PhD Candidate); Haoyuan Li, MD; Xucheng Hou, PhD; Diana D. Kang, BS (PhD Candidate/Icahn Mount Sinai and Ohio State University); Zhengwei Liu, PhD; Meng Tian, PhD; Leiming Wang, PhD; Dinglingge Cao, PhD; Yang Yu, PhD (Ohio State University), Jayce Liu, BS (PhD Candidate, Ohio State University), Xiaolin Cheng, PhD (Ohio State University), Tamara Markovic, PhD; Alice Hashemi, BS; Brian H. Kopell, MD, and Alexander W. Charney, MD, PhD.
