Ethical challenges for a new generation of early-phase pediatric gene therapy trials
pediatrics; ethics; human; review; clinical trial (topic); patient selection; patient engagement; risk benefit analysis; gene therapy; giant axonal neuropathy
After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities. Drawing on our experience as clinical investigators, basic scientists, and bioethicists involved in a first-in-human GT trial for an ultrarare pediatric disease, we analyze these ethical challenges and offer points to consider for future GT trials. Copyright © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
Iyer AA; Saade D; Bharucha-Goebel D; Foley AR; Averion GM; Paredes E; Gray S; Bonnemann CG; Grady C; Hendriks S; Rid A
Genetics in Medicine
2021
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/s41436-021-01245-3" target="_blank" rel="noreferrer noopener">10.1038/s41436-021-01245-3</a>
Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes
Congenital anomalies; genetic condition; prenatal; Clinical management; exome sequencing
Purpose: Previous studies have reported that prenatal exome sequencing (pES) can detect monogenic diseases in fetuses with congenital anomalies with diagnostic yields ranging from 6% to 81%, but there are few reports of its clinical utility. Method(s): We conducted a retrospective chart review of patients who had pES to determine whether results led to clinical management changes. Result(s): Of 20 patients, 8 (40%) received a definitive diagnosis. Seven patients (35%) had medical management changes based on the pES results, including alterations to their delivery plan and neonatal management (such as use of targeted medications, subspecialty referrals, additional imaging and/or procedures). All patients who received a definitive diagnosis and one who received a likely pathogenic variant (n = 9; 45%) received specific counseling about recurrence risk and the medical/developmental prognosis for the baby. In five (25%) cases, the result facilitated a diagnosis in parents and/or siblings. Conclusion(s): pES results can have significant impacts on clinical management, some of which would not be possible if testing is deferred until after birth. To maximize the clinical utility, pES should be prioritized in cases where multiple care options are available and the imaging findings alone are not sufficient to guide parental decision-making, or where postnatal testing will not be feasible. Copyright © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
Tolusso LK; Hazelton P; Wong B; Swarr DT
Genetics in Medicine
2021
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/s41436-020-01067-9" target="_blank" rel="noreferrer noopener">10.1038/s41436-020-01067-9</a>
Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield
Aged; Critical Illness; exome sequencing; Exome/genetics; Genetic Testing; Humans; Infant; Infant Newborn; intensive care unit; neonates; Phenotype; Prospective Studies; Whole Exome Sequencing
PURPOSE: To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria. METHODS: Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team. RESULTS: A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies. CONCLUSION: Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.
Gubbels CS; VanNoy GE; Madden JA; Copenheaver D; Yang S; Wojcik MH; Gold NB; Genetti CA; Stoler J; Parad RB; Roumiantsev S; Bodamer O; Beggs AH; Juusola J; Agrawal PB; Yu TW
Genetics in Medicine
2020
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/s41436-019-0708-6" target="_blank" rel="noreferrer noopener">10.1038/s41436-019-0708-6</a>