Delivery Remains a Leading Challenge for CRISPR Gene Editing Treatments in the Brain

Since the first characterization of a CRISPR locus, all the way back in 1993, researchers have been exploring ways to use gene editing and therapies to treat patients across a spectrum of diseases and syndromes. From that research, Cas9 has emerged as a promising mechanism for applying therapies in specific use cases.

Today, a primary challenge facing CRISPR-Cas9 therapies is delivery. Specifically regarding brain treatments, the blood brain barrier (BBB) prevents Cas9 delivery vehicles from successfully deploying CRISPR gene editing. Most attempts at creating such a vehicle are stymied by the small size required for delivery and the presence of ribonuclease.

The nanoscale required to get Cas9 complexes through the BBB complicates other facets of design. As Cas9 complexes rely on guide RNA, premature exposure to ribonuclease degrades the complex, rendering it useless. Yet, coating a delivery vehicle that is only tens of nanometers in length is challenging from a design and engineering standpoint.

A breakthrough on this front occurred in 2019 when a team at the University of Wisconsin-Madison published research showing how they successfully deployed CRISPR gene editing resources across the BBB. The secret to success is found in two design choices.

First, the delivery vehicle was sized at roughly 30 nanometers in length. That left it barely large enough to hold the Cas9 complex while small enough to pass the BBB. The second choice was the use of angiopep-2 peptide. By dotting it across a polymer shell, the peptide prevented any buildup of surface charge on the vehicle. This prevented any attraction of ribonuclease which, in turn, allowed the Cas9 complex to reach its target without degradation.

This presents a non-invasive alternative to the more popular Cas9 delivery mechanism, viral vectors. Before this breakthrough, viral vectors proved the most reliable way to get a Cas9 complex safely through the bloodstream and into target cells. Naturally, deploying viruses in this way introduces countless complications to the therapy. The UW-Madison research team has now proven a viable alternative that removes viral vectors from the equation.

The capsule-driven therapy is effective too.

With this improved delivery mechanism, CRISPR gene editing therapies have undergone extensive testing for applications in glioblastoma treatments. Test subject mice that received the treatment showed promising results. The therapy increased the mean survival time by 283 percent. Meanwhile, the undesired genetic mutation rate was less than 0.5 percent in untreated brain tissue. For comparison, some comparable lentiviral delivery vectors observe off-target effects on the order of one percent.

This set of experiments shows that CRISPR gene editing therapies are every bit as promising as originally theorized. With additional innovations and continued efforts, Cas9 treatments can target a number of specific health problems, and the potential efficacy rate is extraordinary.

The most exciting realms of discovery lie ahead. CRISPR-Cas9 treatments provide non-invasive measures that can target problematic tissues with extraordinary precision. The potential to remove brain tumors without surgery and with minimal risks could revolutionize neuroscience, and Cas9 treatments that utilize manufactured delivery vehicles certainly have applications far beyond the realm of glioblastoma.