Correcting Genetic Spelling Errors With Next-Generation Crispr

Sam Barnes was my friend. With a sage’s wisdom, he inspired me and many others on how to make the most of life. Affected by a rare disease ProgeriaHis body aged at a rapid rate, and he died of heart failure at just 17, a brave life cut too short.

My lab discovered the genetic cause of Sam’s illness two decades ago: just one DNA letter gone wrong, a T that should have been a C in a complex gene called lamin A. The same misspelling is found in about 200 individuals. The world with progeria.

A few years ago the possibility of dealing with this illness by correcting the misspelling directly in the relevant body tissue was science fiction. then Crispr Along came – elegant enzymatic machinery that allowed DNA scissors to be delivered to a specific target in the genome. In December 2023, FDA approves first Crispr-based therapy For sickle cell disease. The procedure required removing bone marrow cells from the body, making a disabling cut in a specific gene that controls fetal hemoglobin, treating the patient with chemotherapy to make room in the marrow, and then reimplanting the edited cells. Relief from lifelong anemia and excruciating bouts of pain is now being delivered to sickle cell patients, albeit at a steep price.

For progeria and thousands of other genetic diseases, there are two reasons why this same approach won’t work. First, the desired editing for most misspellings cannot usually be achieved by disabling the gene. Instead, a correction is needed. In progeria, the disease-causing T must be edited back to C. According to a word processor analogy, what is needed is not “find and delete” (first generation Crispr), it is “find and replace” (next generation Crispr). Second, the wrong spelling needs to be repaired in the parts of the body that are most affected by the disease. Although bone marrow cells, immune cells and skin cells can be taken out of the body to administer gene therapy, this will not work when the underlying problem is in the cardiovascular system (as in progeria) or in the brain (as in very rare genetic diseases). In the language of gene therapists, we need alive alternative

The exciting news in 2025 is that both of these barriers are starting to come down. The next generation of CRISPR-based gene editors, particularly elegantly pioneered by David Liu of the Broad Institute, allows precise corrective editing of misspellings in virtually any gene without inducing a scission. For delivery systems, the adeno-associated virus (AAV) family of vectors already offers the ability to achieve alive editing in the eye, liver and muscle, although much work remains to be done to optimize delivery and ensure safety in other tissues. Nonviral delivery systems such as lipid nanoparticles are under intense development and may displace viral vectors within a few years.

Working with David Liu, Sam Barnes’ mother, and Leslie Gordon of the Progeria Research Foundation, my research group has already shown that a single intravenous infusion alive Gene editors can dramatically extend the lifespan of mice engineered to carry the human progeria mutation. Our team is now working to advance this to a human clinical trial. We’re really excited about the prospect of children with Progeria, but that excitement can have an even bigger impact. This strategy, if successful, could be a model for the estimated 7,000 genetic diseases where the specific misspellings that cause the disease are known, but no therapy exists.

There are many barriers, cost being a major reason why private investment is absent for a disease that affects only a few hundred people. However, a few rare disease successes supported by government and philanthropic funding will likely lead to efficiencies and economics that will aid other future applications. It is the best hope for millions of children and adults who are waiting for a cure. The rare-disease community needs to press on. That’s what Sam Barnes wanted.