Published in the November 25 online issue of Nature Biotechnology [https://doi.org/10.1038/s41587-024-02487-7], the study introduces a first-of-its-kind 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).
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.
The BCC platform takes advantage of a specialized 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.
“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 author 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.”
The study showed that when the researchers injected a compound called BCC10 linked to specialized 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 (a motor neuron disease), 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, say the investigators.
Despite recent progress in the field, there is still a pressing need for technologies that can bypass the blood-brain barrier and improve the delivery of biomacromolecule-based therapies to the central nervous system via 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 author 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 further studies in large animal models 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.”
The remaining authors, all with Icahn Mount Sinai except where 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.
To view details on competing interests, see: [https://doi.org/10.1038/s41587-024-02487-7].
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About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight- member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
Ranked 11th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 4,560 full-time scientists, educators, and clinicians work within and across 45 academic departments and 38 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases.
Icahn Mount Sinai offers highly competitive MD, PhD, and Master’s degree programs, with current enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,685 clinical residents and fellows training throughout the Health System. In addition, more than 560 postdoctoral research fellows are in training within the Health System.
A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into healthcare products and services that benefit the public.
Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs.
Through the Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.
The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem, and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
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