Sam Burns c 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 ProgeriaHis body aged at a rapid rate, and he died of heart failure at just 17, a heroic life cut 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 critical gene called lamin A. The same misspelling is found in almost all 200 individuals. The world with Progeria.
The possibility of solving this disease by directly correcting the misspelling in the relevant body tissues was only science fiction a few years ago. then crisper came up with – elegant enzymatic apparatus that allows the delivery of DNA scissors to a specific target in the genome. In December 2023, FDA approves first Crispr-based therapy For sickle cell disease. This approach requires removing bone marrow cells from the body, making an inoperable cut in a specific gene that regulates fetal hemoglobin, treating the patient with chemotherapy to make room in the marrow, and then repopulating the edited cells. was Relief from lifelong anemia and excruciating pain attacks is now being offered to sickle cell patients, albeit at a high cost.
For Progeria and thousands of other genetic diseases, there are two reasons why this same approach won’t work. First, the editing required for most misspellings will generally not be achieved by inefficient cuts 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 is needed is not “find and delete” (first generation Crispr), it is “find and replace” (next generation Crispr). Second, the misalignment needs to be repaired in the parts of the body most damaged 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 when the main problem is in the cardiovascular system (as in progeria) or in the brain (as in progeria). that in many rare genetic diseases). In the language of gene therapists, 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, particularly brilliantly pioneered by David Liu of the Broad Institute, allows precise corrective editing of misspelled words of virtually any gene, without cutting scissors. is As for delivery systems, the adeno-associated virus (AAV) family of vectors already provides the ability to in vivo editing in the eye, liver, and muscle, although much work remains to optimize delivery to other tissues and ensure safety. Non-viral delivery systems such as lipid nanoparticles are under intense development and may displace viral vectors in a few years.
Working with David Liu, Sam Burns’ mom, and Leslie Gordon of the Progeria Research Foundation, my research group has already shown that a single infusion of in vivo Gene editors can dramatically extend the lives of mice engineered to carry the human progeria mutation. Our team is now working to bring it forward to human clinical trials. We’re really excited about the prospect of babies with Progeria, but that excitement can have an even bigger impact. This strategy, if successful, could be a model for about 7,000 genetic diseases where the specific misspelling that causes the disease is known, but no cure exists.
There are many barriers, cost being a major one as private investment is absent for diseases that affect only a few hundred individuals. However, success for some rare diseases, supported by government and philanthropic funding, will likely lead to efficiencies and economies that will help in other future applications. This is the best hope for the millions of children and adults who are waiting for treatment. The rare-disease community needs to press. That’s what Sam Burns wanted.
