Sam Burns was a friend of mine. With his sage wisdom, he has inspired me and many others on how to get the most out of life. His brave life was cut short all too soon as he suffered from a rare disease called progeria, which caused his body to age rapidly and died of heart failure at just 17 years old.
My lab discovered the genetic cause of Sam’s disease 20 years ago. Only one DNA letter was wrong, the T in an important gene called Lamin A, which should have been the C. The same spelling mistake was found in almost all of the 200 people around me. A world with progeria.
The opportunity to address this disease by directly correcting misspellings in the relevant body tissues was just science fiction a few years ago. Then came Chrispr, an elegant enzymatic device that can deliver DNA scissors to specific targets within the genome. In December 2023, the FDA approved the first Crispr-based treatment for sickle cell disease. This approach requires removing bone marrow cells from the body, making a disabling cut to a specific gene that controls fetal hemoglobin, treating the patient with chemotherapy to free up space in the bone marrow, and reinjecting the edited cells. There was. Lifelong relief from anemia and bouts of excruciating pain is now being offered to sickle cell patients, albeit at a very high price.
There are two reasons why this same approach doesn’t work for progeria and thousands of other genetic diseases. First, the desired edits for most misspellings are usually not achieved by truncations that disable genes. Instead, a fix is required. For progeria, the disease-causing T must be edited back to C. To use a word processing analogy, you don’t need to “find and delete” (first generation Chrispr), you need “find and replace” (next generation Crispr). Secondly, you need to repair the spelling mistakes in the parts of the body that are most damaged by the disease. Bone marrow cells, immune cells, and skin cells can also be removed outside the body for gene therapy, but if the main problem is in the cardiovascular system (as in progeria) or the brain (as in many rare diseases). It doesn’t work. genetic diseases). In gene therapist jargon, this requires: in vivo option.
The exciting news for 2025 is that both of these barriers are starting to disappear. The next generation of Chrispr-based gene editors, especially elegantly developed by David Liu at the Broad Institute, can accurately correct misspellings in virtually any gene without cutting it with scissors. In terms of delivery systems, the family of adeno-associated virus (AAV) vectors already offers the ability to: in vivo Editing in the eye, liver, and muscle is possible, but much work is still needed 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.
In collaboration with Sam Burns’ mother, David Liu, and Lesley Gordon of the Progeria Research Foundation, my research group has already shown that with a single intravenous infusion of the Progeria Research Foundation, in vivo Gene editors can be used to dramatically extend the lifespan of mice engineered to carry human progeria mutations. Our team is currently working to take this into human clinical trials. We’re really excited about the possibilities for children with progeria, but that excitement could have an even bigger impact. If successful, this strategy could serve as a model for about 7,000 genetic diseases for which we know the specific misspelling that causes the disease, but for which there is no cure.
There are many hurdles and cost is a major challenge as private investment is not available for a disease that affects only a few hundred people. But success in a few rare diseases, with support from governments and philanthropic foundations, will bring efficiencies and economics that will help other applications in the future. This is the greatest hope for tens of millions of children and adults waiting for treatment. The rare disease community must continue to strive. That’s probably what Sam Burns would have wanted.
