What if, instead of trying to fix different gene mutations for different people, one could simply replace the entire mutated gene, safely, efficiently and precisely?
University of Hawaiʻi at Mānoa John A. Burns School of Medicine (JABSOM) Assistant Professor Jesse B. Owens is turning this radical idea into a therapeutic reality. Owens and his team are developing a new gene delivery platform that could revolutionize how doctors treat everything from rare blood disorders to aggressive cancers.
"I want to replace the entire gene, no matter where the mutation is—use one therapy for everyone," said Owens. "For example, if the gene were a car and one person had a flat tire, and another person had a broken windshield; instead of going to two different shops to do two different repairs, each person just got a brand-new car right away, for no more than the cost of the repair. This could lead to faster, more affordable treatments for a wide range of diseases."
What is gene therapy?
The thousands of genes that determine traits and characteristics of humans—including looks, personality and body functions—stem from the long, twisted, step-ladder of molecules known as deoxyribonucleic acid (DNA). Each step or base, makes up the body's genetic code, an instruction manual that dictates how cells build and function. Changes to, or mutations in one's genes can cause genetic disorders such as hemophilia, cystic fibrosis, sickle cell disease and even certain types of cancer.
For decades, researchers have been developing and advancing gene therapies to fix, replace or switch faulty genes in order to treat and prevent diseases. Most approaches use engineered viruses or editing tools to deliver the corrective DNA into a patient's cells.
One of the most widely used gene therapies today is known as Clustered Regularly Interspaced Palindromic Repeats or CRISPR, co-developed by Hilo native Jennifer Doudna, who earned the Nobel Prize in Chemistry in 2020. CRISPR works like a pair of scissors, cutting DNA at specific locations, then harnessing the cell's repair system in hopes that it figures out how to modify or insert the new gene. CRISPR, however, faces limitations—it struggles to insert large DNA segments to fix single-gene disorders, risks harmful mutations and cancer from double-stranded breaks, and works poorly in the non-dividing cells that make up most of the adult human body.
From cutting to inserting: A paradigm shift
Owens' technology represents a dramatic departure from the CRISPR paradigm. Rather than cutting DNA and relying on the cell to make repairs, his method acts like biological glue—actively inserting large, healthy genes directly into the genome that then take over for the defective gene. The key is a family of viral enzymes called integrases, which facilitate the insertion of DNA into host genomes. Owens' lab uses a controlled process called "laboratory evolution" to engineer "super-active" enzymes, dramatically boosting their precision and efficiency for inserting genes of interest.
"With these specially engineered integrases, we're able to carefully insert healthy genes into an exact location without causing breaks in the DNA," said Owens. "This insertion function has very high efficiencies of up to 96% in human cells, which is unprecedented."
