Sam Berns is 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 old age diseaseHis body aged at a rapid rate and he died of heart failure at the age of 17, a brave life cut too short.
My lab discovered the genetic cause of Sam's disease two decades ago: Just one DNA letter was wrong, a T that should have been a C, in a key gene called lamin A. Similar spelling errors were found in almost every 200 individuals around the world. The world has progeria
The opportunity to tackle this disease by directly correcting spelling errors in the body tissues involved was science fiction just a few years ago. Afterward sharp was born—the elegant enzymatic machinery that allows DNA scissors to be delivered to a specific target in the genome. In December 2023, The FDA has approved the first Crispr-based therapy for sickle cell disease. That approach entails removing bone marrow cells from the body, performing an ablation of a specific gene that regulates fetal hemoglobin, treating the patient with chemotherapy to make room for the marrow, and then infusing the patient with chemotherapy. edited cells again. A cure for lifelong anemia and excruciating pain is now being delivered to sickle cell patients, despite the high cost.
For progeria and thousands of other genetic diseases, there are two reasons why this approach doesn't work. First, the desired correction of most misspellings is usually not achieved by silencing genes. Instead, an adjustment is needed. In the case of progeria, the pathogenic T needs to be edited to a C. Similar to a word processor, what is needed is not “find and delete” (first generation Crispr), but “find and replacement” ( Crispr next generation). Second, spelling errors need to be corrected in the parts of the body most damaged by disease. Although bone marrow cells, immune cells, and skin cells can be removed from the body to perform gene therapy, that will not be effective when the main problem is in the cardiovascular system (such as progeria) or the brain (as in many rare cases). genetic disease). In the language of the gene therapist, we need alive option.
The exciting news in 2025 is that both of these barriers are starting to lift. The next generation of Crispr-based gene editors, pioneered especially by the Broad Institute's David Liu, allows for precise editing of virtually any gene misspelling without the need for scissoring. For delivery systems, the adeno-associated virus (AAV) family of vectors has provided the ability to achieve alive correction 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 being actively developed and may replace viral vectors in the next few years.
Working with David Liu, Sam Berns' mother, and Leslie Gordon of the Progeria Research Foundation, my research team has shown that a single intravenous infusion of a drug alive Gene editing can significantly extend the lifespan of mice engineered to carry mutations in the human progeria gene. Our team is currently working to advance this product into human clinical trials. We're really excited about the potential for children with progeria, but that excitement could have an even bigger impact. This strategy, if successful, could be a model for some 7,000 genetic diseases for which the specific misspelling that causes the disease is known but for which there is no treatment.
There are many obstacles, of which cost is a major issue because of the lack of private investment in diseases that affect only a few hundred individuals. However, success in some rare diseases, supported by government and philanthropic foundations, will likely yield efficiencies and economics that will benefit 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. That's what Sam Berns wants.