General & Reproductive Genetics
The beginning of in vivo gene editing—the beginning of a new phase in medicine
We recently witnessed the beginning of a new period in medicine with the announcement of the first ever personalized gene-editing case in which an infant with carbamoyl-phosphate synthetase 1(CPS1) deficiency was treated at roughly age of seven months,1 rightly in a Science Behind the Study article described as a milestone in the evolution of personalized therapies for rare and ultra rare inborn errors of metabolism.2
CPS1 is recessively inherited and is exceedingly rare (estimates range between 1/1,300,000 and 1/800,00 births). It affects CPS1, a mitochondrial enzyme that catalyzes the first and rate-limiting step of the urea cycle, the conversion (primarily in hepatocytes) of ammonia and bicarbonate to carbamoyl phosphate. If dysfunctional, ammonia accumulates in blood, which is toxic to the brain, leading to coma and death shortly after birth in ca. 50% of cases if left untreated.2
Here, the investigators immediately after birth of the infant started developing a so-called “base-editor” which can correct disease-causing abnormal genetic variants, in this case, a customized lipid nanoparticle delivering base editing therapy, of which the infant received two infusions. Already in the seventh week after the first infusion, the infant was able to tolerate an increased amount of dietary protein (and reduced dose of nitrogen-scavenger medication, the usual treatment, to half of its usual dose).
Authors as well as commentators, of course, pointed out the preliminary nature of these results, but nobody can argue with the fact that a new phase in medicine has started.
References
Musunuru et al., N Engl J Med 2025;392(22):2235-2243
Gropman AL, Komor AC. N Engl J Med 2025;392(22):2273-2276
BRCA1 and BRCA2 effects on ovarian reserve
Even though they did not give the CHR credit in referencing earlier work on the subject at the CHR,1 we want to give colleagues from Brown University in Providence, RI, credit for demonstrating in a Research Letter in Fertility and Sterility once again the fact that women with BRCA1 and BRCA 2 mutations demonstrate lower functional ovarian reserve than controls.2 Moreover, their finding also suggest that DNA damage may be the cause. Interestingly, they found similar effects with BRCA1 as well as BRCA2, while we noted this effect only in BRCA1 patients.
Fortunately, BRCA mutations are relatively rare, but when they occur, one should be aware of this fact. Moreover, evidence for premature ovarian aging (POA) at a young age should be a reason for a BRCA evaluation. Since BRCA testing no longer carries with itself any longer the horrible expenses patients had to accept until several years ago had to accept, testing in such cases should be routine, especially with breast and some other cancer histories in the family.
Now, one reads increasingly that especially BRCA1 testing should become part of prenatal carrier screening in obstetrical care, which, of course, also would mean in the routine first testing round in fertility clinics.3
References
Oktay et al., J Clin Onc 2009;27(15suppl):11039
Ou et al., Fertil Steril 2025;123(5):899-901
Dioun et al., Am J Obstet Gynecol 2024;231(3):330e1-330e14
The Cost-Benefits of Performing BRCA1 Testing as Part of Prenatal Carrier Screening. NewYork-Presbyterian Advances. Published 2025. https://www.nyp.org/advances/article/the-cost-benefits-of-performing-brca1-testing-as-part-of-prenatal-carrier-screening