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9. Towards germline gene therapy of inherited mitochondrial diseases

Author

Tachibana, Masahito, Amato, Paula, Sparman, Michelle, Woodward, Joy, Sanchis, Dario Melguizo, Ma, Hong, Gutierrez, Nuria Marti, Tippner-Hedges, Rebecca, Kang, Eunju, Lee, Hyo-Sang, Ramsey, Cathy, Masterson, Keith, Battaglia, David, Lee, David, Wu, Diana, Jensen, Jeffrey, Patton, Phillip, Gokhale, Sumita, Stouffer, Richard, and Mitalipov, Shoukhrat

Subjects
Genetic disorders -- Research, Gene therapy -- Usage -- Methods, Mitochondrial DNA -- Diseases and pests, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg's cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle-chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls., Mitochondrial DNA is localized in the cell's cytoplasm, whereas chromosomal genes are confined to the nucleus. Each cell may have thousands of mtDNA copies, which may all be mutated (homoplasmy) [...]

Published
2013
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46. Overriding follicle selection in controlled ovarian stimulation protocols: Quality vs quantity

Author

Zelinski-Wooten Mary B and Stouffer Richard L

Subjects
Gynecology and obstetrics, RG1-991, Reproduction, QH471-489
Abstract

Abstract Selection of the species-specific number of follicles that will develop and ovulate during the ovarian cycle can be overridden by increasing the levels of pituitary gonadotropin hormones, FSH and LH. During controlled ovarian stimulation (COS) in nonhuman primates for assisted reproductive technology (ART) protocols, the method of choice (but not the only method) has been the administration of exogenous gonadotropins, either of nonprimate or primate origin. Due to species-specificity of the primate LH (but not FSH) receptor, COS with nonprimate (e.g., PMSG) hormones can be attributed to their FSH activity. Elevated levels of FSH alone will produce large antral follicles containing oocytes capable of fertilization in vitro (IVF). However, there is evidence that LH, probably in lesser amounts, increases the rate of follicular development, reduces heterogeneity of the antral follicle pool, and improves the viability and rate of pre-implantation development of IVF-produced embryos. Since an endogenous LH surge typically does not occur during COS cycles (especially when a GnRH antagonist is added), a large dose of an LH-like hormone (i.e., hCG) may be given to reinitiate meiosis and produce fertilizable oocytes. Alternate approaches using exogenous LH (or FSH), or GnRH agonist to induce an endogenous LH surge, have received lesser attention. Current protocols will routinely yield dozens of large follicles with fertilizable eggs. However, limitations include non/poor-responding animals, heterogeneity of follicles (and presumably oocytes) and subsequent short luteal phases (limiting embryo transfer in COS cycles). However, the most serious limitation to further improvements and expanded use of COS protocols for ART is the lack of availability of nonhuman primate gonadotropins. Human, and even more so, nonprimate gonadotropins are antigenic in monkeys, which limits the number of COS cycles to as few as 1 (PMSG) or 3 (recombinant hCG) protocols in macaques. Production and access to sufficient supplies of nonhuman primate FSH, LH and CG would overcome this major hurdle.

Published
2004
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47. Insulin-like growth factor 2 is produced by antral follicles and promotes preantral follicle development in macaques†

Author

Tkachenko, Olena Y, Wolf, Shally, Lawson, Maralee S, Ting, Alison Y, Rodrigues, Jhenifer K, Xu, Fuhua, Bishop, Cecily V, Stouffer, Richard L, and Xu, Jing

Abstract

Insulin-like growth factors (IGFs) are known for their involvement in endocrine and paracrine regulation of ovarian function. Although IGF2 is the predominant circulating and intraovarian form of IGFs in primate species, the stage-specific follicular expression, action, and regulation of IGF2 are not well defined. Therefore, experiments were conducted to investigate the follicular IGF production in response to steroid hormone regulation and the direct IGF actions on follicular development and function in vitro. Preantral follicles were isolated from rhesus macaque ovaries and cultured to the antral stage in media supplemented with follicle-stimulating hormone and insulin. Follicles were randomly assigned to treatment groups: (a) control, (b) trilostane (a steroid synthesis inhibitor), (c) trilostane + estradiol, (d) trilostane + progesterone, and (e) trilostane + dihydrotestosterone. Media was analyzed for IGF concentrations, which were correlated to follicle growth. Follicles produced IGF2, but not IGF1, at the antral stage. Steroid depletion decreased, whereas steroid replacement increased, IGF2 production by antral follicles. Media IGF2 levels correlated positively with antral follicle diameters. Macaque preantral follicles and granulosa cells were subsequently cultured without (control) and with recombinant human IGF2 supplementation. Follicle survival, growth, and paracrine factor production, as well as granulosa cell proliferation and gonadotropin receptor gene expression, were assessed. IGF2 addition increased follicle survival rates, diameters and inhibin B production, as well as granulosa cell proliferation. These data demonstrate that IGF2 produced by antral follicles, in response to steroid hormone regulation, could act as a paracrine factor that positively impacts preantral follicle development and function in primates.Insulin-like growth factor 2, but not insulin-like growth factor 1, is produced by antral follicles in response to steroid hormone regulation in nonhuman primates, and promotes preantral follicle growth with increased paracrine factor production.

Published
2021
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