Sam Berns was my friend. With the wisdom of a sage, he inspired me and many others about how to make the most of life. Afflicted with the rare disease called progeria, his body aged at a rapid rate, and he died of heart failure at just 17, a brave life cut much too short.
My lab discovered the genetic cause of Sam’s illness two decades ago: Just one DNA letter gone awry, a T that should have been a C in a critical gene called lamin A. The same misspelling is found in almost all of the 200 individuals around the world with progeria.
The opportunity to address this illness by directly fixing the misspelling in the relevant body tissues was just science fiction a few years ago. Then Crispr came along—the elegant enzymatic apparatus that allows delivery of DNA scissors to a specific target in the genome. In December 2023, the FDA approved the first Crispr-based therapy for sickle cell disease. That approach required taking bone marrow cells out of the body, making a disabling cut in a particular gene that regulates fetal hemoglobin, treating the patient with chemotherapy to make room in the marrow, and then reinfusing the edited cells. A relief from lifelong anemia and excruciating attacks of pain is now being delivered to sickle cell patients, albeit at very high cost.
For progeria and thousands of other genetic diseases, there are two reasons why this same approach won’t work. First, the desired edit for most misspellings will not usually be achieved by a disabling cut in the gene. Instead, a correction is needed. In the case of progeria, the disease-causing T needs to be edited back to a C. By analogy with a word processor, what’s needed is not “find and delete” (first-generation Crispr), it’s “find and replace” (next-generation Crispr). Second, the misspelling needs to be repaired in the parts of the body that are 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, that won’t work 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 the gene therapist, we need in vivo options.
The exciting news in 2025 is that both of these barriers are starting to come down. The next generation of Crispr-based gene editors, pioneered particularly elegantly by David Liu of the Broad Institute, allows precise corrective editing of virtually any gene misspelling, without inducing a scissors cut. As for delivery systems, the family of adeno-associated virus (AAV) vectors already provides the ability to achieve in vivo editing in eye, liver, and muscle, though there is still much work 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 displace viral vectors in a few years.
Working with David Liu, Sam Berns’ mom, and Leslie Gordon of the Progeria Research Foundation, my research group has already shown that a single intravenous infusion of an in vivo gene editor can dramatically extend the life of mice that have been engineered to carry the human progeria mutation. Our team is now working to bring this forward to a human clinical trial. We are truly excited about the potential for kids with progeria, but that excitement could have even greater impact. This strategy, if successful, could be a model for the approximately 7,000 genetic diseases where the specific misspelling that causes the disease is known, but no therapy exists.
There are many hurdles, cost being a major one as private investment is absent for diseases that affect only a few hundred individuals. However, success for a few rare diseases, supported by government and philanthropic funds, will likely lead to efficiencies and economies that will help with other future applications. This is the best hope for the tens of millions of children and adults who are waiting for a cure. The rare-disease community must press on. That’s what Sam Berns would have wanted.
