New nanoparticles deliver whole-brain therapy, edit Alzheimer’s gene in mice

UW–Madison researchers engineered silicon nanoparticles to cross the blood-brain barrier in mice, enabling whole-brain gene-editing therapy for Alzheimer’s disease. photograph: Jeff Miller

Gene therapy has the potential to treat neurological disorders such as Alzheimer’s disease and Parkinson’s disease, but faces a common barrier: the blood-brain barrier. Researchers at the University of Wisconsin-Madison are now developing ways to transcend the brain’s protective membranes to deliver treatments throughout the brain using a variety of biologic medications and treatments.

Shaoqin “Sarah” Gong University of Wisconsin-Madison

‘Many devastating brain disorders still have no cure,’ says Shaoqin “Sarah” Gong, UW-Madison Professor of Ophthalmology and Visual Sciences and Biomedical Engineering, and Researcher at the Wisconsin Institute for Discovery. “Innovative brain-targeted delivery strategies may lead to genome-editing therapies for these diseases by enabling non-invasive, safe and efficient delivery of CRISPR genome editors.”

CRISPR is a molecular toolkit for editing genes (e.g., to fix mutations that can cause disease), but this toolkit is only useful if it can get through security and into the field. . The blood-brain barrier is a membrane that selectively controls access to the brain and excludes toxins and pathogens that may be present in the bloodstream. Unfortunately, this barrier prevents beneficial therapies such as certain vaccines and gene therapy packages from reaching their targets.

Injecting therapeutics directly into the brain is one way to bypass the blood-brain barrier, but it is an invasive procedure that only provides access to nearby brain tissue.

“The feasibility of brain gene therapy and genome editing therapies relies on the safe and efficient delivery of nucleic acids and genome editors throughout the brain,” says Gong.

A study recently published in the journal advanced materialsGong and members of her lab, including Yuyuan Wang, a postdoctoral researcher and lead author of the study, carried genome-editing tools to many organs around the body and then dissolved them harmlessly, made of silica. A new family of nanoscale capsules is described.

By modifying the surface of silica nanocapsules with fragments derived from glucose and amino acids, rabies virus, researchers found that nanocapsules could efficiently cross the blood-brain barrier to achieve gene editing throughout the mouse brain. In their study, researchers demonstrated the ability of CRISPR cargoes in silica nanocapsules to successfully edit genes in the mouse brain, including one associated with Alzheimer’s disease called the amyloid precursor protein gene.

Nanocapsules can be administered intravenously repeatedly, thus achieving greater therapeutic efficacy without compromising more local and invasive methods.

The researchers plan to further optimize the brain-targeting ability of silica nanocapsules and evaluate their utility for the treatment of various brain disorders. This unique technology is also being investigated for delivery of biologics to the eye, liver and lungs, and may lead to new gene therapies for other types of diseases.

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