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Principles of and strategies for germline gene therapy

Published on Jun 3, 2019in Nature Medicine 30.64
· DOI :10.1038/s41591-019-0473-8
Don P. Wolf42
Estimated H-index: 42
(OHSU: Oregon Health & Science University),
Paul A. Mitalipov (OHSU: Oregon Health & Science University), Shoukhrat Mitalipov36
Estimated H-index: 36
(OHSU: Oregon Health & Science University)
Monogenic disorders occur at a high frequency in human populations and are commonly inherited through the germline. Unfortunately, once the mutation has been transmitted to a child, only limited treatment options are available in most cases. However, means of correcting disease-causing nuclear and mitochondrial DNA mutations in gametes or preimplantation embryos have now been developed and are commonly referred to as germline gene therapy (GGT). We will discuss these novel strategies and provide a path forward for safe, high-efficiency GGT that may provide a promising new paradigm for preventing the passage of deleterious genes from parent to child.
  • References (80)
  • Citations (0)
Published on Mar 1, 2019in Nature 43.07
Eric S. Lander245
Estimated H-index: 245
Françoise Baylis23
Estimated H-index: 23
+ 15 AuthorsDavid R. Liu69
Estimated H-index: 69
Eric Lander, Francoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg and specialists from seven countries call for an international governance framework. Eric Lander, Francoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg and specialists from seven countries call for an international governance framework.
Published on Feb 28, 2019in Science 41.04
Shuai Jin3
Estimated H-index: 3
(CAS: Chinese Academy of Sciences),
Yuan Zong6
Estimated H-index: 6
(CAS: Chinese Academy of Sciences)
+ 8 AuthorsFeng Zhang104
Estimated H-index: 104
(UMN: University of Minnesota)
Cytosine and adenine base editors (CBEs and ABEs) are promising new tools for achieving the precise genetic changes required for disease treatment and trait improvement. However, genome-wide and unbiased analyses of their off-target effects in vivo are still lacking. Our whole genome sequencing (WGS) analysis of rice plants treated with BE3, high-fidelity BE3 (HF1-BE3), or ABE revealed that BE3 and HF1-BE3, but not ABE, induce substantial genome-wide off-target mutations, which are mostly the C→...
Published on Nov 30, 2018in Nature 43.07
David Cyranoski31
Estimated H-index: 31
Startling human-genome editing claim leaves many open questions, from He Jiankui's next move to the future of the field. Startling human-genome editing claim leaves many open questions, from He Jiankui's next move to the future of the field.
Published on Nov 1, 2018in Nature Medicine 30.64
Sandra R. Bacman14
Estimated H-index: 14
(UM: University of Miami),
Johanna H.K. Kauppila4
Estimated H-index: 4
(MPG: Max Planck Society)
+ 7 AuthorsCarlos T. Moraes67
Estimated H-index: 67
(UM: University of Miami)
Mutations in the mitochondrial DNA (mtDNA) are responsible for several metabolic disorders, commonly involving muscle and the central nervous system1. Because of the critical role of mtDNA in oxidative phosphorylation, the majority of pathogenic mtDNA mutations are heteroplasmic, co-existing with wild-type molecules1. Using a mouse model with a heteroplasmic mtDNA mutation2, we tested whether mitochondrial-targeted TALENs (mitoTALENs)3,4 could reduce the mutant mtDNA load in muscle and heart. AA...
Published on Nov 1, 2018in Nature Medicine 30.64
Payam A. Gammage10
Estimated H-index: 10
(MRC Mitochondrial Biology Unit),
Carlo Viscomi22
Estimated H-index: 22
(MRC Mitochondrial Biology Unit)
+ 13 AuthorsRaffaele Cerutti6
Estimated H-index: 6
(MRC Mitochondrial Biology Unit)
Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a pro...
Published on Oct 1, 2018in Nature Medicine 30.64
Avery C. Rossidis2
Estimated H-index: 2
(Children's Hospital of Philadelphia),
John D. Stratigis3
Estimated H-index: 3
(Children's Hospital of Philadelphia)
+ 14 AuthorsWenjian Lv3
Estimated H-index: 3
(UPenn: University of Pennsylvania)
In utero gene editing has the potential to prenatally treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. We assessed the viral vector–mediated delivery of CRISPR–Cas9 or base editor 3 in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1, respectively. We observed long-term postnatal persistence of edited cells in both models, with reduction of plasma PCSK9 and choles...
Published on Jul 16, 2018in Nature Biotechnology 31.86
Michael Kosicki2
Estimated H-index: 2
Kärt Tomberg5
Estimated H-index: 5
Allan Bradley112
Estimated H-index: 112
Cas9-induced double stranded breaks can cause large deletions near the target site and more complex genomic rearrangements in mouse and human stem cells.
Published on Sep 1, 2018in Nature Medicine 30.64
G Massaro4
Estimated H-index: 4
(UCL: University College London),
Citra Nurfarah Zaini Mattar12
Estimated H-index: 12
(NUS: National University of Singapore)
+ 19 AuthorsSimon Heales15
Estimated H-index: 15
(GOSH: Great Ormond Street Hospital)
For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross t...
Published in Nature 43.07
Dieter Egli34
Estimated H-index: 34
(Columbia University),
Michael V. Zuccaro1
Estimated H-index: 1
(Columbia University)
+ -3 AuthorsMaria Jasin11
Estimated H-index: 11
(MSK: Memorial Sloan Kettering Cancer Center)
Cited By0
Published in Journal of Medical Ethics 2.19
Bryan Cwik2
Estimated H-index: 2
(PSU: Portland State University)
Design of clinical trials for germline gene editing stretches current accepted standards for human subjects research. Among the challenges involved is a set of issues concerning intergenerational monitoring—long-term follow-up study of subjects and their descendants. Because changes made at the germline would be heritable, germline gene editing could have adverse effects on individuals’ health that can be passed on to future generations. Determining whether germline gene editing is safe and effe...