CRISPR is a marvelous development that allows for removing or altering a gene within a cell with great precision. Emmanuelle Charpentier and Jennifer Doudna created the highly targeted gene-editing method and received the Nobel Prize in chemistry for it this year.
The method is currently being used or tested for treating patients with sickle cell anemia and cancers, including liposarcoma and multiple myeloma. However, there’s no way yet to target the treatment to specific locations in the body. Instead, the procedure involves removing immune system T cells or blood stem cells from the patient to modify them and then infuse them back to reconstitute an immune response or repopulate the bloodstream. It’s a time-consuming and expensive process.
Hence, a group of Tufts biomedical engineers, led by associate professor Qiaobing Xu, decided to build on Charpentier and Doudna’s accomplishments by developing a way to deliver gene-editing packages directly. They constructed a gene-editing “kit” that could be injected to do its work inside the body on targeted cells.
In experiments with mice, it crossed into immune system cells, made its way to specific tissues and organs, and even crossed the blood-brain barrier into particular regions of the brain. These applications could lead to a new treatment method for infectious disease, autoimmune diseases, cancer, and neurological conditions.
The scientists used tiny “bubbles” of lipid molecules called lipid nanoparticles (LNPs) to envelop the editing enzymes and deliver them to specific cells, organs, or tissues. The team had to modify the surface of the LNPs so they could stick to cells and fuse with their membranes. Once attached, the LNPs release the gene-editing enzyme into the cells.
Xu said:
We created a method around tailoring the delivery package for a wide range of potential therapeutics, including gene editing. The methods draw upon combinatorial chemistry used by the pharmaceutical industry for designing the drugs themselves. Still, instead, we are applying the approach to designing the components of the delivery vehicle.
To get medicines to breach the brain barrier has been a long-standing challenge in medicine. Among the team’s accomplishments with the new method include:
- The delivery of a CRISPR kit consisting of an entire complex of messenger RNAs and enzymes into targeted brain areas in a living animal.
- The delivery of the small molecule antifungal drug amphotericin B (for treatment of meningitis) into the brain.
- The delivery of a DNA fragment that binds to and shuts down the gene producing the tau protein linked to Alzheimer’s disease into the brain.
- The delivery of gene-editing packages into T-cells in mice.
The LNPs that fuse with T-cells deliver gene-editing contents that can alter the cells’ molecular makeup and behavior. T-cells help destroy infected cells before viruses can replicate, produce antibodies, and suppress, or regulate other immune system cells. Using this method, they can make the immune system more robust by engineering it to fight diseases better.
Xu said:
By targeting T cells, we can tap into a branch of the immune system that has tremendous versatility in fighting off infections, protecting against cancer, and modulating inflammation and autoimmunity.
The team’s next step is to explore further the mechanism by which LNPs find their way to a target within the body. The experiments with mice went well, but many more studies need to be conducted to determine the safety and efficacy of the delivery method in humans.
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