UCLA researchers from the Department of Neurology have developed synthetic exosomes, a novel delivery technology capable of transporting gene-editing tools and therapeutics across the blood-brain barrier, with successful applications in repairing Alzheimer’s-related mutations and delivering proteins, antibodies, and drugs.
BACKGROUND: The emergence of gene-editing technologies has revolutionized the potential treatment of genetic diseases. Many debilitating diseases, such as Sickle Cell Disease and Alzheimer’s Disease, arise from single point mutations that could be corrected through precision gene-editing tools like CRISPR. These approaches rely on the delivery of guide RNAs and specialized enzymes to target and repair specific mutations. However, for gene editing therapies to effectively treat neurological genetic disorders, they must first overcome the challenge of crossing the blood brain barrier (BBB), a highly selective membrane that restricts the passage of most therapeutics, including small molecules, proteins, and nucleic acids. Developing efficient delivery systems capable of transporting gene-editing components into the nervous system is therefore a critical step in unlocking the full therapeutic potential of these groundbreaking technologies.
INNOVATION: UCLA researchers have developed a brain delivery technology, termed synthetic exosomes (SEs), designed to encapsulate and transport macromolecules, including gene-editing components. They successfully utilized SEs to deliver RNA, including the the mRNA encoding the CRISPR enzyme Cas9, to the mouse brain, and demonstrated precise genetic modification. Notably, they leveraged this technology to repair a point mutation associated with an increased risk of Alzheimer’s Disease in a mouse model after IV administration, and demonstrating delivery across the BBB. Beyond gene-editing applications, researchers have successfully used SEs to encapsulate antibodies and a zoledronate drugs, highlighting their versatility as a novel platform for targeted therapy. This technology paves the way for new treatments of neurological diseases, overcoming the challenge of crossing the BBB to unlock the full potential of emerging therapeutics.
POTENTIAL APPLICATIONS:
- Delivering gene-editing tools to the nervous system and for targeted therapy in human disease
- Delivering diverse therapeutics, such as antibodies, proteins, or other small molecules to tissues
- Therapeutic delivery method for other tissues (such as muscle and liver)
ADVANTAGES:
- Increased delivery efficiency across the BBB
- Tunable delivery platform (size, Zeta potential, surface functionalization)
- Manufactured with Generally Regarded As Safe (GRAS) materials
- Large-scale continuous production enabled by microfluidic reactor synthesis
- Suitable for long-term storage as lyophilized powder
- Can be delivered systemically for used for gene editing of multiple tissue types
DEVELOPMENT-TO-DATE: UCLA researchers have developed synthetic exosomes and validated their ability to successfully encapsulate and deliver proteins and RNA, including CRISPR editing components, in vitro, as well as to the brain in a mouse model.
Related Papers (from the inventors only):
- Teter, B., Campagna, J., Zhu, C., McCauley, G. E., Spilman, P., Kohn, D. B., & John, V. (2024). Successful gene editing of apolipoprotein E4 to E3 in brain of Alzheimer model mice after a single IV dose of synthetic exosome-delivered CRISPR. BioRxiv.
- Campagna et. al., eLife 2022, 11:276207.
- Campagna J, et. al., Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery. Journal of Drug Delivery. 2017; 2017:4759839.
Keywords: Nanovesicles, CRISPR, gene-editing, exosomes, synthetic biology, Alzheimer’s Disease, delivery system, nanotechnology.