US2016024527A1PendingUtilityA1
Compositions and Methods for Enhancing Bioenergetic Status in Female Germ Cells
Est. expiryJun 29, 2031(~4.9 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 15/08C12N 5/0682C07D 277/587C07D 277/64A61K 35/54A61K 35/51A61K 35/14A61K 35/28C07D 233/88C12N 15/873A61K 31/4745C07D 233/60C12N 2517/10C07D 495/04A61K 31/137A61K 31/277C12N 5/0609A61K 31/498C07D 213/50C07D 277/36C12N 2501/40A61K 31/352A61K 31/05
50
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Claims
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.
Claims
exact text as granted — not AI-modified1 . A composition comprising an isolated cell selected from the group consisting of an oocyte, an oogonial stem cell (OSC) or the progeny of an OSC, and a bioenergetic agent.
2 . The composition of claim 1 , wherein the bioenergetic agent is selected from the group consisting of tryptophan, quinolinic acid, nicotinamide mononucleotide, nicotinamide riboside, nicotinic acid, fisetin, quercetin, resveratrol, DOI, hydroxytyrosol, pyrroloquinoline quinone, metformin, apigenin, luteolin, tryphostin 8, berberine and a CD38 inhibitor, and functional derivatives thereof.
3 . The composition of claim 1 , wherein the bioenergetic agent is a compound of any one of formulas I-XV:
wherein
is an aryl heterocycle diradical;
is heteroaryl;
X is halo;
R 1 is hydroxy, alkoxy, or amino; and
R 2 is hydroxy, alkoxy, or amino;
wherein, independently for each occurrence,
is heteroaryl;
X is halo;
R 2 is hydroxy, alkoxy, or amino; and
Y is —O— or —NH—;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino; and
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino; and
R 1 is hydroxy, alkoxy, or amino;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R1 is hydroxy, alkoxy, or amino;
R 3 is —H, cyano, —CO 2 R 4 , or —C(O)N(R 4 ) 2 ; and
R 4 is —H or alkyl;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino; and
R 1 is hydroxy, alkoxy, or amino;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
X is halo;
Y 1 is —O—, —S—, or —NH—; and
Y 2 is ═N— or ═CR—;
wherein, independently for each occurrence,
is a five-membered, unsaturated heterocycle diradical;
is heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino; and
Y 2 is ═N— or ═CR—;
wherein, independently for each occurrence,
is heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
Y 1 is —S—, —O—, or —NH—;
wherein, independently for each occurrence,
is an aryl heterocycle diradical;
is heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino; and
Y 2 is ═N— or ═CR—;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino; and
Y 1 is —S—, —O—, or —NH—;
wherein, independently for each occurrence,
is aryl or heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino;
R 2 is hydroxy, alkoxy, or amino;
R 3 is —H, cyano, —CO 2 R 4 , or —C(O)N(R 4 ) 2 ;
X is halo;
Y 3 is a bond, —C(O)-d, —C(O)NH-d, —NH—C(O)-d, or —C(O)NH—CH 2 -d; and
d is a bond to
wherein, independently for each occurrence,
is a five-membered heterocycle radical;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino;
R 2 is hydroxy, alkoxy, or amino; and
X is halo; and
wherein, independently for each occurrence,
is aryl or heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino;
R 2 is hydroxy, alkoxy, or amino;
R 3 is —H, cyano, —CO 2 R 4 , or —C(O)N(R 4 ) 2 ;
X is halo;
Y 3 is a bond, —C(O)-d, —C(O)NH-d, —NH—C(O)-d, or —C(O)NH—CH 2 -d; and
d is a bond to
4 . The composition of claim 1 , further comprising a solution selected from the group consisting of cell culture medium, oocyte retrieval solution, oocyte washing solution, oocyte in vitro maturation medium, ovarian follicle in vitro maturation medium, oocyte in vitro fertilization medium, vitrification solution and cryopreservation solution.
5 . The composition of claim 1 , wherein the OSC is an isolated non-embryonic stem cell that is mitotically competent and expresses Vasa, Oct-4, Dazl, Stella and optionally a stage-specific embryonic antigen.
6 . The composition of claim 1 , wherein the OSC is obtained from ovarian tissue or from non-ovarian tissue.
7 . The composition of claim 1 , wherein the bioenergetic agent is selected from the group consisting of tryptophan, quinolinic acid, nicotinamide mononucleotide, nicotinamide riboside, nicotinic acid, fisetin, quercetin, resveratrol, DOI, hydroxytyrosol, pyrroloquinoline quinone, metformin, apigenin, luteolin, tryphostin 8, berberine and a CD38 inhibitor, a compound of any one of formulas I-XV:
wherein
is an aryl heterocycle diradical;
is heteroaryl;
X is halo;
R 1 is hydroxy, alkoxy, or amino; and
R 2 is hydroxy, alkoxy, or amino;
wherein, independently for each occurrence,
is heteroaryl;
X is halo;
R 2 is hydroxy, alkoxy, or amino; and
Y is —O— or —NH—;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino; and
Y 1 is —S—, —O—, or —NH—;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino; and
R 1 is hydroxy, alkoxy, or amino;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R1 is hydroxy, alkoxy, or amino;
R 3 is —H, cyano, —CO 2 R 4 , or —C(O)N(R 4 ) 2 ; and
R 4 is —H or alkyl;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino; and
R 1 is hydroxy, alkoxy, or amino;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
X is halo;
Y 1 is —O—, —S—, or —NH—; and
Y 2 is ═N— or ═CR—;
wherein, independently for each occurrence,
is a five-membered, unsaturated heterocycle diradical;
is heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino; and
Y 2 is ═N— or ═CR—;
wherein, independently for each occurrence,
is heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
Y 1 is —S—, —O—, or —NH—;
wherein, independently for each occurrence,
is an aryl heterocycle diradical;
is heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino; and
Y 2 is ═N— or ═CR—;
wherein, independently for each occurrence,
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino; and
Y 1 is —S—, —O—, or —NH—;
wherein, independently for each occurrence,
is aryl or heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino;
R 2 is hydroxy, alkoxy, or amino;
R 3 is —H, cyano, —CO 2 R 4 , or —C(O)N(R 4 ) 2 ;
X is halo;
Y 3 is a bond, —C(O)-d, —C(O)NH-d, —NH—C(O)-d, or —C(O)NH—CH 2 -d; and
d is a bond to
wherein, independently for each occurrence,
is a five-membered heterocycle radical;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino;
R 2 is hydroxy, alkoxy, or amino; and
X is halo; and
wherein, independently for each occurrence,
is aryl or heteroaryl;
R is —H, halo, aryl, nitro, alkyl, hydroxy, alkoxy, or amino;
R 1 is hydroxy, alkoxy, or amino;
R 2 is hydroxy, alkoxy, or amino;
R 3 is —H, cyano, —CO 2 R 4 , or —C(O)N(R 4 ) 2 ;
X is halo;
Y 3 is a bond, —C(O)-d, —C(O)NH-d, —NH—C(O)-d, or —C(O)NH—CH 2 -d; and
d is a bond to
and
functional derivatives thereof.
8 . The composition of claim 76 , wherein the non-ovarian tissue is blood.
9 . The composition of claim 76 , wherein the non-ovarian tissue is bone marrow.
10 . The composition of claim 1 , wherein the composition comprises ovarian tissue, ovarian follicles, bone marrow, umbilical cord blood or peripheral blood.
11 . An isolated cell having enhanced mitochondrial function relative to a reference, wherein the cell is selected from the group consisting of an oocyte, an oogonial stem cell (OSC) or the progeny of an OSC, wherein the cell has been contacted with a bioenergetic agent.
12 - 23 . (canceled)
24 . A composition comprising OSC mitochondria or oocyte mitochondria and the bioenergetic agent recited in claim 7 .
25 - 34 . (canceled)
35 . An isolated mitochondria, wherein said isolated mitochondria has been contacted with the bioenergetic agent recited in claim 3 .
36 . An isolated mitochondria, wherein said isolated mitochondria has been contacted with the bioenergetic agent recited in claim 2 .
37 - 47 . (canceled)
48 . An isolated cell-free composition comprising OSC mitochondria or oocyte mitochondria and the bioenergetic agent recited in claim 7 .
49 - 53 . (canceled)
54 . A method of preparing an oocyte for in vitro fertilization (IVF), the method comprising transferring a composition comprising OSC mitochondria and the bioenergetic agent recited in claim 7 into an autologous oocyte, thereby preparing said oocyte for in vitro fertilization.
55 - 63 . (canceled)
64 . An oocyte prepared according to the method of claim 54 .
65 . A method of in vitro fertilization, said method comprising the steps of:
a) incubating an OSC from a female subject with the bioenergetic agent recited in claim 7 ; b) obtaining a composition comprising OSC mitochondria from the OSC; c) transferring the composition into an isolated, autologous oocyte; and d) fertilizing the autologous oocyte in vitro to form a zygote.
66 - 67 . (canceled)
68 . A method of preparing an oocyte for in vitro fertilization, the method comprising transferring a composition comprising oocyte mitochondria and the bioenergetic agent recited in claim 7 into an autologous oocyte, thereby preparing said oocyte for in vitro fertilization.
69 - 70 . (canceled)
71 . An oocyte prepared according to the method of claim 68 .
72 . A method of in vitro fertilization, said method comprising the steps of:
a) incubating an oocyte from a female subject with the bioenergetic agent recited in claim 7 , and functional derivatives thereof; b) obtaining a composition comprising oocyte mitochondria from the oocyte; c) transferring the composition into an isolated, autologous oocyte; and d) fertilizing the autologous oocyte in vitro to form a zygote.
73 - 74 . (canceled)
75 . A method of in vitro fertilization, said method comprising the steps of:
a) incubating an oocyte from a female subject with the bioenergetic agent recited in claim 7 ; and b) fertilizing the oocyte in vitro to form a zygote.
76 . A composition comprising a solution selected from the group consisting of cell culture medium, oocyte retrieval solution, oocyte washing solution, oocyte in vitro maturation medium, ovarian follicle in vitro maturation medium, oocyte in vitro fertilization medium, embryo culture medium, cleavage medium, vitrification solution, cryopreservation solution and embryo thawing medium and the bioenergetic agent recited in claim 7 .
77 . A method of improving fertility in a female subject, said method comprising administering to the subject the bioenergetic agent recited in claim in an amount effective to improve oocyte and/or OSC quality, de novo production and/or ovulated oocyte yield, thereby improving fertility in the female subject.
78 - 80 . (canceled)
81 . A method of in vitro fertilization, said method comprising the steps of:
a) administering to a female subject the bioenergetic agent recited in claim 7 in an amount effective to improve oocyte and/or OSC de novo production, quality and/or ovulated oocyte yield; b) obtaining an oocyte from the female subject; and c) fertilizing the oocyte in vitro to form a zygote.
82 - 87 . (canceled)
88 . A method of sustaining embryonic development in a pregnant female subject in need thereof, said method comprising administering to the subject the bioenergetic agent recited in claim 7 thereby sustaining embryonic development in the pregnant female subject.
89 - 90 . (canceled)
91 . A method of restoring or increasing ovarian function in a female subject in need thereof, comprising administering a therapeutically effective amount of the bioenergetic agent recited in claim 7 , thereby restoring ovarian function in the female subject.
92 - 94 . (canceled)
95 . A method of preparing a tissue or cell thereof from a female subject for harvest, said method comprising administering an effective amount of the bioenergetic agent recited in claim 7 to the female subject, thereby preparing said tissue or cell thereof from the female subject for harvest.
96 - 97 . (canceled)
98 . A method of producing an oocyte, comprising culturing a stem cell selected from the group consisting of an OSC, embryonic stem cell, pancreatic stem cell, skin stem cell and induced pluripotent stem cell (iPS cell) in the presence of the bioenergetic agent recited in claim 7 , under conditions sufficient to differentiate the stem cell into an oocyte.
99 - 100 . (canceled)
101 . A composition comprising an isolated cell selected from the group consisting of an oocyte, an oogonial stem cell (OSC) or the progeny of an OSC and a bioenergetic agent for use in in vitro fertilization.
102 . An isolated cell having enhanced mitochondrial function relative to a reference, wherein the cell is selected from the group consisting of an oocyte, an oogonial stem cell (OSC) or the progeny of an OSC, wherein the cell has been contacted with a bioenergetic agent for use in in vitro fertilization.
103 . A bioenergetic agent for use in one or more of the group consisting of: improving the fertility of a female, sustaining embryonic development in a pregnant female, restoring or increasing ovarian function in a female, preparing a tissue or cell thereof from a female for harvest and preparing an oocyte, wherein the bioenergetic agent is as recited in claim 7 .Join the waitlist — get patent alerts
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