Sam Burns was my friend. With the wisdom of a sage, he inspired me and many others on how to make the most of life. suffering from a rare disease called progeriaHis body began to age rapidly and he died of heart failure at the age of just 17, an adventurous life cut too short.
My lab discovered the genetic cause of Sam's disease two decades ago: Just one DNA letter was messed up, a T that should have been a C, in a vital gene called lamin A. The same misspelling is found in nearly all of the approximately 200 individuals in the world with progeria.
The opportunity to remedy this disease by directly correcting the misspelling in the relevant body tissues was just science fiction a few years ago. Then crisper Came along – beautiful enzymatic tool that allows delivery of DNA scissors to a specific target in the genome. In December 2023, FDA approves first Crispr-based therapy For sickle cell disease. That approach involves taking bone marrow cells out of the body, making a disabling cut in a particular gene that controls fetal hemoglobin, treating the patient with chemotherapy to create space in the marrow, and then reinfusing the edited cells. were required. Sickle cell patients are now being given relief from lifelong anemia and unbearable attacks of pain, although at a 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 edits for most misspellings will generally not be achieved by inefficient cuts in the gene. Instead, there is a need for improvement. In the case of progeria, the disease-causing T needs to be edited back to C. By analogy with word processors, what is needed is not “find and delete” (first generation Crisp), it is “find and replace” (next generation Crisp). Second, misspellings must be repaired in those parts of the body 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, this will not work if the main problem is in the cardiovascular system (as in progeria) or the brain (as in many rare cases. Have genetic disease. We need gene therapists in language in vivo Option.
The exciting news in 2025 is that both of these barriers are beginning 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 misspelled genes of virtually any gene, without cutting with scissors. As far as delivery systems are concerned, the family of adeno-associated virus (AAV) vectors already offers the potential to achieve in vivo editing in the eye, liver and muscle, although much work still remains to optimize delivery to other tissues and ensure safety. Non-viral delivery systems such as lipid nanoparticles are under intensive development and may displace viral vectors within a few years.
Working with David Liu, Sam Burns' mother, and Leslie Gordon of the Progeria Research Foundation, my research group has already shown that a single intravenous infusion in vivo The gene editor could dramatically extend the lives of mice that have been engineered to carry the human progeria mutation. Our team is now working to bring it into human clinical trials. We're really excited about the prospect of having children with progeria, but that excitement could have an even bigger impact. If successful, this strategy could lead to a model for some 7,000 genetic diseases where the specific misspelling that causes the disease is known, but no treatment exists.
There are several barriers to this, the major one being cost as private investment is absent for diseases affecting only a few hundred individuals. However, success in some rare diseases supported by government and philanthropic funding will likely lead to efficiencies and economies of scale that will help other future applications. This is the best hope for millions of children and adults who are waiting for treatment. The rare disease community must move forward. That's what Sam Burns would have wanted.