We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.
PURPOSE: Monochorionic twins (MC) have twofold higher mortality than dichorionic twins (DC) and fourfold higher when compared to singletons. We analyzed the development of weight discordance and the average time of diagnosis/morbidity in MC.METHODS: Retrospective analysis of the intertwin weight discordance during pregnancy in Twin-Twin Transfusion Syndrome (TTTS) and Selective Intrauterine Growth Retardation (sIUGR), using a linear mixed model and single-factor analysis of variance in a cohort of MC at our institution. RESULTS: In a cohort of 143 MC the development of the intertwin weight difference varies significantly between uncomplicated and pathologic MC (P<0,001). An intertwin weight difference is detectable starting with the 16th weeks’ of gestation, however, the first diagnosis is routinely made in the 21 weeks’ gestation (20.6 ± 3.9 TTTS, 19.6 ± 3.4 sIUGR). Compared to concordant MC, both TTTS and sIUGR had increased mortality with higher rates of intrauterine fetal demise (18.2% vs. 7.7%; P=0.243) and antenatal corticosteroids (85,7% vs. 65,2%). Delivered 2-3 weeks earlier, pathologic twins had a lower birth weight, lower APGAR and pH values, and a higher demand for neonatal intensive care for longer periods. Artificial reproduction techniques resulted in a 3.6-fold increased risk of developing TTTS (38.4% vs. 21.9%, P = 0.061) and sIUGR (30.8% vs. 21.9%, P=0.061).CONCLUSIONS: The mortality and morbidity in MC highly correlates with the stage and time of the initial diagnosis. Expediting diagnosis and treatment, starting with the 16th week of gestation could arguably decrease intrauterine fetal demise, neurological morbidity, and prematurity.
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