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Sam Berns was my friend. With the wisdom of a sage, he inspired me and many others on how to make the most of life. Afflicted with the rare disease called progeriahis body aged at a rapid rate, and he died of heart failure at only 17 years old, a brave life cut too short.
My lab discovered the genetic cause of Sam’s disease two decades ago: A single DNA letter gone wrong, a T that should have been a C in a critical gene called lamin A. The same misspelling occurs in almost all 200 individuals around the world with progeria.
The opportunity to deal with this disease by directly correcting the spelling error in the relevant body tissues was only science fiction a few years ago. So what Crispr has arrived – the elegant enzymatic apparatus that enables the delivery of DNA scissors to a specific target in the genome. In December 2023, the The FDA has approved the first therapy based on Crispr for sickle cell disease. That approach required removing bone marrow cells from 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. Relief from lifelong anemia and excruciating pain attacks is now being delivered to sickle cell disease patients, albeit at a very high cost.
For progeria and thousands of other genetic diseases, there are two reasons why this same approach doesn’t work. First, the editing desired for most spellings will not generally be achieved by a disabling cut in the gene. Instead, a correction is needed. In the case of progeria, the T that causes the disease must be edited back to a C. By analogy with a word processor, what is needed is not “find and delete” (first generation Crispr), it is “find and replace” (next generation Crispr). Second, the misspelling must be repaired in the parts of the body that are most damaged by the disease. While bone marrow cells, immune cells and skin cells can be removed from the body to administer gene therapy, that does not work when the main problem is in the cardiovascular system (such as in progeria) or in the brain (as in many rare). genetic diseases). In the lingo of the genetic therapist, we need alive options.
The exciting news in 2025 is that both barriers will begin to come down. The next generation of Crispr-based gene editors, particularly elegantly pioneered by the Broad Institute’s David Liu, allows accurate correct editing of almost any gene misspelling, without inducing a scissor cut. In terms of delivery systems, the adeno-associated virus (AAV) family of vectors already provides the ability to achieve this. alive edition in the eye, liver and muscle, although there is still a lot of work to be done to optimize delivery to other tissues and ensure safety. Non-viral delivery systems, such as lipid nanoparticles, are under intense development and may replace viral vectors within a few years.
Working with David Liu, the mother of Sam Berns, and Leslie Gordon of the Progeria Research Foundation, my research group has already shown that a single intravenous infusion of a alive The gene editor can dramatically extend the lives of mice that have been engineered to carry the human progeria mutation. Our team is now working to bring this to a human clinical trial. We are really excited about the potential for children with progeria, but this excitement could have an even bigger impact. This strategy, if successful, could be a model for about 7,000 genetic diseases where the specific spelling that causes the disease is known, but no therapy exists.
There are many obstacles, the cost is a big one, since private investment is absent for diseases that affect only a few hundred individuals. However, the success for a few rare diseases, supported by the government and philanthropic funds, will probably 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 waiting for a cure. The rare disease community must press on. That’s what Sam Berns would have wanted.
