Towards germline gene therapy of inherited mitochondrial diseases

Tachibana, Masahito; Amato, Paula; Sparman, Michelle; Woodward, Joy; Melguizo‐Sanchis, Dario; Ma, Hong; Gutiérrez, Nuria Martí; Tippner-Hedges, Rebecca; Kang, Eunju; Lee, Hyo Sang; Ramsey, Cathy; Masterson, Keith; Battaglia, David E.; Lee, David; Wu, Diana; Jensen, Jeffrey T.; Patton, Phillip E.; Gokhale, Sumita; Stouffer, Richard L.; Mitalipov, Shoukhrat

doi:10.1038/nature11647

Cited by 382 publications

(373 citation statements)

References 23 publications

(35 reference statements)

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“…Controlled ovarian stimulation. Research oocyte donors were evaluated before study inclusion as previously reported; standard IVF protocols and procedures for ovarian stimulation were described previously 44 . Oocyte donation cycles were managed by OHSU Fertility physicians.…”

Section: Methodsmentioning

confidence: 99%

Correction of a pathogenic gene mutation in human embryos

Martí-Gutiérrez

Park

et al. 2017

Nature

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More than 10,000 monogenic inherited disorders have been identified, affecting millions of people worldwide. Among these are autosomal dominant mutations, where inheritance of a single copy of a defective gene can result in clinical symptoms. Genes in which dominant mutations manifest as late-onset adult disorders include BRCA1 and BRCA2, which are associated with a high risk of breast and ovarian cancers 1 , and MYBPC3, mutation of which causes hypertrophic cardiomyopathy (HCM) 2 . Because of their delayed manifestation, these mutations escape natural selection and are often transmitted to the next generation. Consequently, the frequency of some of these founder mutations in particular human populations is very high. For example, the MYBPC3 mutation is found at frequencies ranging from 2% to 8% 3 in major Indian populations, and the estimated frequency of both BRCA1 and BRCA2 mutations among Ashkenazi Jews exceeds 2% 4 .HCM is a myocardial disease characterized by left ventricular hypertrophy, myofibrillar disarray and myocardial stiffness; it has an estimated prevalence of 1:500 in adults 5 and manifests clinically with heart failure. HCM is the commonest cause of sudden death in otherwise healthy young athletes. HCM, while not a uniformly fatal condition, has a tremendous impact on the lives of individuals, including physiological (heart failure and arrhythmias), psychological (limited activity and fear of sudden death), and genealogical concerns. MYBPC3 mutations account for approximately 40% of all genetic defects causing HCM and are also responsible for a large fraction of other inherited cardiomyopathies, including dilated cardiomyopathy and left ventricular non-compaction 6 . MYBPC3 encodes the thick filament-associated cardiac myosin-binding protein C (cMyBP-C), a signalling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of both contraction and relaxation 2 .Current treatment options for HCM provide mostly symptomatic relief without addressing the genetic cause of the disease. Thus, the development of novel strategies to prevent germline transmission of founder mutations is desirable. One approach for preventing second-generation transmission is preimplantation genetic diagnosis (PGD) followed by selection of non-mutant embryos for transfer in the context of an in vitro fertilization (IVF) cycle. When only one parent carries a heterozygous mutation, 50% of the embryos should be mutationfree and available for transfer, while the remaining carrier embryos are discarded. Gene correction would rescue mutant embryos, increase the number of embryos available for transfer and ultimately improve pregnancy rates.Recent developments in precise genome-editing techniques and their successful applications in animal models have provided an option for correcting human germline mutations. In particular, CRISPR-Cas9 is a versatile tool for recognizing specific genomic sequences and inducing DSBs 7-10 . DSBs are then resolved by endogenous DNA repair mechanisms, prefer...

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Section: Methodsmentioning

confidence: 99%

Correction of a pathogenic gene mutation in human embryos

Martí-Gutiérrez

Park

et al. 2017

Nature

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815

540

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“…To this end, we utilized fresh MII oocytes donated by and retrieved from 11 healthy volunteers (25-31 years) following controlled ovarian stimulation (COS) protocols and transvaginal follicular aspirations (Tachibana et al, 2013b).…”

Section: De Novo Formation Of MII Spindles From the Pb1 Genomesmentioning

confidence: 99%

Functional Human Oocytes Generated by Transfer of Polar Body Genomes

O’Neil

Gutiérrez

et al. 2017

Cell Stem Cell

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“…21). Yet, there are regulatory means in place that in fact prevent human germline modifications in publicly funded research and in clinical settings.…”

Section: Illusion Of (Universal) Controlmentioning

confidence: 99%

The illusion of control in germline-engineering policy

König

2017

Nat Biotechnol

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correlation between gCSI and CTRP data sets is significantly increased using GR AOC rather than AUC as a response metric (P = 1.3 × 10 -3 , Student's t-test; Supplementary Fig. 4).And third, efficacy as measured by GR max and potency as measured by GR 50 differ at a biological level, carry complementary information (low mutual information), and are associated with largely non-overlapping genetic alterations. In principle, variation in potency and efficacy can be captured by integrating across dose-response curves (GR AOC ), but we find that information content is maximized if GR 50 and GR max are considered independently.Because the ultimate purpose of antineoplastic drugs is to kill cancer cells 13 , and high potency is no guarantee of good efficacy, we propose that the best drugs and most important pharmacogenomic associations are not those associated with low IC 50 values, but rather those that result in the most negative GR value at clinically relevant drug concentrations (e.g., C max ). Relating in vitro measures of drug sensitivity to in vivo responses remains challenging 17 , but for this to have any chance of success it is essential that in vitro data are as informative and reproducible as possible. Editor's note: This article has been peer-reviewed.

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Towards germline gene therapy of inherited mitochondrial diseases

Cited by 382 publications

References 23 publications

Correction of a pathogenic gene mutation in human embryos

Correction of a pathogenic gene mutation in human embryos

Functional Human Oocytes Generated by Transfer of Polar Body Genomes

The illusion of control in germline-engineering policy

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