Compositions and Methods for Enhancing Bioenergetic Status in Female Germ Cells

Abstract

Compositions and methods comprising bioenergetic agents for restoring the quality of aged oocytes, enhancing oogonial stem cells or improving derivatives thereof (e.g., cytoplasm or isolated mitochondria) for use in fertility-enhancing procedures, are described.

Description

CROSS-REFERENCE TO RELATED SUBJECT MATTER[0001]This application is a continuation of U.S. Ser. No. 13 / 447,083, filed Apr. 13, 2012, pending, which claims benefit under 35 U.S.C. §119(e) of U.S. provisional application Ser. Nos. 61 / 502,840, filed Jun. 29, 2011, and U.S. provisional application Ser. No. 61 / 600,529, filed Feb. 17, 2012. The entire disclosures of each of the aforementioned patent applications are incorporated herein by reference.STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under contract No. NIH R37-AG012279 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Since the early 1950s, clinical management of problems associated with ovarian insufficiency and failure, including infertility due to aging or insults, has been restricted by the belief that the pool of oocytes set forth at birth is not amenable to replacem...

AI Technical Summary

Benefits of technology

[0012]In another aspect, the invention provides an isolated cell having enhanced mitochondrial function, where the cell is one or more of an oocyte, an oogonial stem cell (OSC) or the progeny of an OSC, where the cell has been contacted with a bioenergetic agent (one or more of soluble precursors to NAD+ (e.g., tryptophan, quinolinic acid, nicotinamide mononucleotide, nicotinamide riboside, and nicotinic acid), fisetin, quercetin, resveratrol, DOI, hydroxytyrosol, pyrroloquinoline quinone, metformin, apigenin, luteolin, tryphostin 8, berberine, a CD38 inhibitor, SRT-1720, SIRT1 activator, a compound of any one of formulas I-XV, or functional derivatives thereof).

[0042]In other embodiments of any of the above aspects or any aspect delineated herein, the mitochondria is in a cell that is one or more of an oocyte, an oogonial stem cell (OSC) or the progeny of an OSC, and a bioenergetic agent. In various embodiments of any of the above aspects or any aspect delineated herein, the cell is in a mixture with ovarian tissue, ovarian follicles, bone marrow, umbilical cord blood or peripheral blood. In still other embodiments, the pregnancy outcomes of the female subject are improved compared to a reference standard. In still other embodiments, the bioenergetic agent is systemically administered to the female subject or is locally administered to an ovary of the female subject.

Problems solved by technology

Although these new studies indicate that oocyte numbers in adult ovaries are amenable to therapeutic expansion through OSC-based technology, ovarian aging and failure is determined by both a decline in oocyte number as well as a decline in the quality of the oocytes present in the ovaries.

The decline in live birth rate reflects a decline in response to ovarian stimulation by gonadotropin hormones (follicle-stimulating hormone or FSH, and luteinizing hormone or LH), reduced oocyte and embryo quality and pregnancy rates, and an increased incidence of miscarriages and fetal aneuploidy.

At present there is no known intervention to improve the pregnancy outcome of older female patients.

However, this approach has significant long-term negative effects on ovarian and uterine function, leading to higher fetal death and resorptions as well as decreased litter frequency and size in treated animals (Tarin et al., Theriogenology 2002 57:1539-1550).

Thus, clinical translation of chronic anti-oxidant therapy throughout reproductive life for maintaining or improving oocyte quality in aging females is impractical.

Cells with low mitochondrial NAD+ are prone to cell dysfunction and death (Yang et al., Cell 2008).

Arguably, the most significant issue with heterologous ooplasmic transfer is tied to the fact that mitochondria also contain genetic material that is distinct from nuclear genes contributed by the biological mother and biological father.

While use of autologous mitochondria from somatic cells would avoid mitochondrial heteroplasmy, the somatic mitochondria are nonetheless inadequate, as they are prone to mitochondrial DNA damage and deletions resulting in heritable mutations.

Importantly, oocytes, which are prone to aging-associated defects, are not of high enough quantity or quality to be reliably used in such procedures.

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