Cell and Gene Therapy: Bringing Cutting-Edge Therapies to Wisconsin

3D rendering of CRISPR-Cas9 replacing DNA segment with matching RNA segment
Pictured: 3D rendering of CRISPR-based genome editing. The Cas9 protein works to replace a DNA sequence with the desired genetic information. This method can be used to replace missing genetic information or insert entirely new synthetic sequences.

Gene therapy has captured the public’s imagination as several products have now been approved for therapeutic use and hundreds more are being tested in clinical trials. In pursuit of this great potential, biomedical engineering associate professor Krishanu “Kris” Saha plans to lead the Grainger Institute for Engineering’s newest impact area, cell and gene therapy, by strengthening these possibilities, edging toward clinical applications.

Though cell and gene therapy has been around for decades, critical developments in genome editing techniques have made novel therapeutics viable. By editing individual genomes of cells within the body, researchers like Saha are able to personalize medical treatments at the level of individual DNA strands.

Krishanu Saha
Krishanu Saha

Researchers in Saha’s lab use the CRISPR-Cas9 technology to edit targeted sections of the genome. The CRISPR-Cas9 system was originally found in bacteria (a discovery recognized this month with the Nobel Prize in Chemistry) and is a naturally occurring editing system. Bioengineers can program it by using a short piece of RNA as a guide and, when the right DNA sequence matching the guide is found, the Cas9 protein works to edit the selected DNA sequence and replace it with the desired genetic information. This method can also be used to replace missing genetic information or insert entirely new synthetic sequences.

“Gene editing allows very targeted, precise modifications to the genome,” Saha says. “Without CRISPR, it was challenging to get the precision and specificity needed to edit the genome one letter at a time.”

Saha’s research team uses CRISPR-Cas9 to tackle inherited eye diseases, like Best disease, and generate new cell immunotherapies. Best disease is a rare disorder in which retinal cells in the eye deform and die early, lowering the ability of retinal tissues to properly detect light. It is caused by a dominant gene mutation. Because CRISPR-Cas9 allows for extremely meticulous targeting, it can be exquisitely programmed to disrupt these problematic mutated genes.

Genome editing can be also used to insert new capabilities into a patient’s own T cells, a type of white blood cell playing an essential role in the immune system, particularly allowing them to target cancer cells. Three FDA-approved T cell products have been recently developed to treat blood cancers. Researchers in Saha’s lab are now using CRISPR-Cas9 to add more functionality to these products, hoping these strategies allow them to treat other tumors, especially solid ones. If successful, these strategies could help the immune system generate new durable treatments for a wide variety of cancers.

Saha closed out 2020 with some promising new genome editing strategies and modeling techniques published in Nature Communications, findings from his lab’s work designing and simulating CRISPR-based genome editors for more complex recessive disorders like Pompe disease.

Looking forward, the real-world applications of Saha’s research are particularly exciting because of their potential impacts in Wisconsin, especially since it is becoming a new research hub within UW’s College of Engineering. Developing this area of research on campus will allow for cross-disciplinary collaboration, spearheading the advancement of the Wisconsin Idea.

“We are hoping to make an impact on patients,” Saha says. “Hopefully, within five to ten years, we are initiating clinical trials—where patients who are seen at UW Health and other Wisconsin residents can take part in many of these trials.”

According to Saha, cell and gene therapy is a rapidly evolving industry, and this allows for the development of a wide range of new ideas. The consistent drive for discovery throughout the field provides a strong basis for creative advancement.

“I think there are all sorts of new creative ideas that come from my trainees as well as others in the field, and it’s a wonderful opportunity to build something new here in Wisconsin with those ideas,” Saha says. “The moments that I am up at night excited about are when I get new results from my team, or I see some dots being connected by a new idea published by this young and vibrant research community.”

As Saha continues to discover and expand cell and gene therapy initiatives, a partnership with the Grainger Institute for Engineering provides resources and connections necessary for advancing even more cutting-edge developments. By connecting a wide variety of knowledge bases and disciplines across engineering, medicine and ethics, Saha hopes the growth in this field can lead to even more important breakthroughs in medicine.

“I see the Grainger Institute for Engineering as having important resources in amplifying the work we want to do in scaling up and scaling out some of the techniques of manufacturing these gene therapies,” Saha says. “It provides an exciting group of people who are thinking with a bold vision to change what we are doing here on campus and beyond.”

Author: Katie Amdahl