Sam Berns is my friend. With his sage wisdom, he inspired me and many others on how to make the most of life. Suffering from a rare disease called progeria, he aged rapidly, and died of heart failure when he was only 17 years old, his brave life was cut too short. letter gone awry, T which should be C in a critical gene called lamin A. The same spelling is found in almost all 200 individuals around the world with progeria. The opportunity to overcome this disease by directly correcting the misspelling in the corresponding body tissue was only science fiction a few years ago. Then came Crispr – an elegant enzymatic apparatus that allows the delivery of DNA scissors to specific targets in the genome. In December 2023, the FDA approved the first Crispr-based therapy for sickle cell disease. The approach involves taking bone marrow cells out of the body, cutting out certain genes that regulate fetal hemoglobin, treating the patient with chemotherapy to make room in the marrow, and then reinfusing the modified cells. A relief from lifelong anemia and exruciating pain attacks are now being sent to sickle cell patients, although at a very high cost. For progeria and thousands of other genetic diseases, there are two reasons why the same approach doesn’t work. First, the desired correction for most misspellings cannot usually be achieved by removing the gene. However, a correction is needed. In the case of progeria, the disease-causing T must be converted back to C. By analogy with word processors, what is needed is not “find and delete” (first generation Crispr), but “find and replace” (next generation Crispr). Second, the wrong spelling should be corrected in the part of the body that is most harmed by the disease. While bone marrow cells, immune cells, and skin cells can be taken out of the body to administer gene therapy, which will not be possible when the main problem is in the cardiovascular system (as in progeria) or the brain (as in many rare genetic diseases). In the lingo of gene therapy, we need selection in vivo. The good news in 2025 is that both barriers are starting to come down. The next generation of Crispr-based gene editors, elegantly pioneered by David Liu of the Broad Institute, allows precise editing correction of almost any gene misspelling, without resulting in scissor cuts. For delivery systems, the adeno-associated virus (AAV) vector family has provided the ability to achieve in vivo editing in the eye, liver, and muscle, although much remains to be done to optimize delivery to other tissues and ensure safety. Nonviral delivery systems such as lipid nanoparticles are under intense development and may replace viral vectors within a few years. Working with David Liu, Sam Berns’ mother, and Leslie Gordon of the Progeria Research Foundation, my research group has shown that one intravenous. infusion of gene editors in vivo can dramatically extend the lifespan of mice that have been engineered to carry the human progeria mutation. Our team is currently working to bring this to human clinical trials. We’re excited about the potential for children with progeria, but that excitement could have an even bigger impact. This strategy, if successful, could serve as a model for the approximately 7,000 genetic diseases where the specific misspelling that causes the disease is known, but there is no therapy. affecting only a few hundred individuals. However, success for some rare diseases, supported by government and philanthropic funds, will likely lead to efficiency and economy that will help with other future applications. This is the best hope for tens of millions of children and adults waiting for a cure. The rare disease community must continue to thrive. That’s what Sam Berns wanted.
