Toward gene therapy of premature ovarian failure

Intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice

M. Ghadami, E. El-Demerdash, S. A. Salama, A. A. Binhazim, A. E. Archibong, X. Chen, B. R. Ballard, M. R. Sairam, Ayman Al-Hendy

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

A homozygous missense mutation, C566T, in the follicle stimulation hormone receptor (FSHR) gene has been linked to premature ovarian failure. The disease leads to infertility in a normal karyotype female with an elevated follicle stimulating hormone (FSH) and decreased serum estrogen level. Female mice carrying mutated FSHR gene, called follitropin receptor knockout (FORKO), display similar phenotype and are sterile because of a folliculogenesis block at a primary stage. We investigated the effects of bilateral intraovarian injection of an adenovirus expressing a normal copy of human FSHR on the reproductive system of 6-10 weeks female FORKO mice. Ad-LacZ was injected directly into each ovary of the control group. Animals were sacrificed at 2, 4, 8 and 12 weeks post-injection and tissues collected for evaluation. Treated mice showed estrogenic changes in daily vaginal smear whereas control animals remained fixated in the diestrus stage. Histological evaluation showed on average 26±4 follicles/ovary in treated group with 8±2 follicles at the antral stage compared with only 5±2 with zero follicles at antral stage in Ad-LacZ control mice. There was no significant change in serum level of progesterone, however, estrogen level increased 2-3-fold (P < 0.02) and FSH decreased by up to 50% (P < 0.04) in treated animals. FSHR mRNA was detected in the ovaries of the treated group. In conclusion, intra-ovarian injection of an adenovirus expressing human FSHR gene is able to restore FSH responsiveness and reinitiate ovarian folliculogenesis as well as resume estrogen production in female FORKO mice. Ad-LacZ injections indicate the absence of systemic viral dissemination or germ line transmission of adenovirus DNA to offspring.

Original languageEnglish (US)
Article numbergaq003
Pages (from-to)241-250
Number of pages10
JournalMolecular Human Reproduction
Volume16
Issue number4
DOIs
StatePublished - Jan 19 2010

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Human Follicle Stimulating Hormone
FSH Receptors
Primary Ovarian Insufficiency
Follicle Stimulating Hormone
Adenoviridae
Knockout Mice
Genetic Therapy
Hormones
Injections
Ovary
Estrogens
Genes
Diestrus
Human Adenoviruses
Vaginal Smears
Missense Mutation
Serum
Karyotype
Germ Cells
Infertility

Keywords

  • FORKO mice
  • Follicle-stimulating hormone receptor
  • Gene therapy of ovarian failure
  • Primary amenorrhea
  • Primary ovarian failure (POF)

ASJC Scopus subject areas

  • Molecular Biology
  • Embryology
  • Cell Biology
  • Genetics
  • Developmental Biology
  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Toward gene therapy of premature ovarian failure : Intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice. / Ghadami, M.; El-Demerdash, E.; Salama, S. A.; Binhazim, A. A.; Archibong, A. E.; Chen, X.; Ballard, B. R.; Sairam, M. R.; Al-Hendy, Ayman.

In: Molecular Human Reproduction, Vol. 16, No. 4, gaq003, 19.01.2010, p. 241-250.

Research output: Contribution to journalArticle

Ghadami, M, El-Demerdash, E, Salama, SA, Binhazim, AA, Archibong, AE, Chen, X, Ballard, BR, Sairam, MR & Al-Hendy, A 2010, 'Toward gene therapy of premature ovarian failure: Intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice', Molecular Human Reproduction, vol. 16, no. 4, gaq003, pp. 241-250. https://doi.org/10.1093/molehr/gaq003
Ghadami, M. ; El-Demerdash, E. ; Salama, S. A. ; Binhazim, A. A. ; Archibong, A. E. ; Chen, X. ; Ballard, B. R. ; Sairam, M. R. ; Al-Hendy, Ayman. / Toward gene therapy of premature ovarian failure : Intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice. In: Molecular Human Reproduction. 2010 ; Vol. 16, No. 4. pp. 241-250.
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abstract = "A homozygous missense mutation, C566T, in the follicle stimulation hormone receptor (FSHR) gene has been linked to premature ovarian failure. The disease leads to infertility in a normal karyotype female with an elevated follicle stimulating hormone (FSH) and decreased serum estrogen level. Female mice carrying mutated FSHR gene, called follitropin receptor knockout (FORKO), display similar phenotype and are sterile because of a folliculogenesis block at a primary stage. We investigated the effects of bilateral intraovarian injection of an adenovirus expressing a normal copy of human FSHR on the reproductive system of 6-10 weeks female FORKO mice. Ad-LacZ was injected directly into each ovary of the control group. Animals were sacrificed at 2, 4, 8 and 12 weeks post-injection and tissues collected for evaluation. Treated mice showed estrogenic changes in daily vaginal smear whereas control animals remained fixated in the diestrus stage. Histological evaluation showed on average 26±4 follicles/ovary in treated group with 8±2 follicles at the antral stage compared with only 5±2 with zero follicles at antral stage in Ad-LacZ control mice. There was no significant change in serum level of progesterone, however, estrogen level increased 2-3-fold (P < 0.02) and FSH decreased by up to 50{\%} (P < 0.04) in treated animals. FSHR mRNA was detected in the ovaries of the treated group. In conclusion, intra-ovarian injection of an adenovirus expressing human FSHR gene is able to restore FSH responsiveness and reinitiate ovarian folliculogenesis as well as resume estrogen production in female FORKO mice. Ad-LacZ injections indicate the absence of systemic viral dissemination or germ line transmission of adenovirus DNA to offspring.",
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