Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for in Vivo Gene Therapy of Uterine Leiomyoma

Mohamed Abdelaziz, Lotfy Sherif, Mostafa Elkhiary, Sanjeeta Nair, Shahinaz Shalaby, Sara Mohamed, Noura Eziba, Mohamed El-Lakany, David Curiel, Nahed Ismail, Michael Peter Diamond, Ayman Al-Hendy

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. Study design: An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Materials and methods: Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR. Results: In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P < 0.05), reduced expression of proliferation marker (PCNA) (P < 0.05), induced expression of apoptotic protein, c-PARP-1, (P < 0.05) and inhibited expression of extracellular matrix-related genes (TGF beta 3) and angiogenesis-related genes (VEGF & IGF-1) (P < 0.01). There were no detectable adenovirus in tested tissues other than leiomyoma lesions with both targeted and untargeted adenovirus. Conclusion: Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial.

Original languageEnglish (US)
Pages (from-to)464-474
Number of pages11
JournalReproductive Sciences
Volume23
Issue number4
DOIs
StatePublished - Apr 1 2016

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Leiomyoma
Genetic Therapy
Adenoviridae
Extracellular Matrix
Transforming Growth Factor beta3
Apoptosis
Lac Operon
Proliferating Cell Nuclear Antigen
Insulin-Like Growth Factor I
Nude Mice
Vascular Endothelial Growth Factor A
Genes
Neoplasms
Analysis of Variance
Animal Models
Western Blotting
Immunohistochemistry
Safety
Polymerase Chain Reaction
Therapeutics

Keywords

  • adenovirus vectors
  • gene therapy
  • thymidine kinase/apoptosis
  • uterine leiomyoma

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Abdelaziz, M., Sherif, L., Elkhiary, M., Nair, S., Shalaby, S., Mohamed, S., ... Al-Hendy, A. (2016). Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for in Vivo Gene Therapy of Uterine Leiomyoma. Reproductive Sciences, 23(4), 464-474. https://doi.org/10.1177/1933719116630413

Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for in Vivo Gene Therapy of Uterine Leiomyoma. / Abdelaziz, Mohamed; Sherif, Lotfy; Elkhiary, Mostafa; Nair, Sanjeeta; Shalaby, Shahinaz; Mohamed, Sara; Eziba, Noura; El-Lakany, Mohamed; Curiel, David; Ismail, Nahed; Diamond, Michael Peter; Al-Hendy, Ayman.

In: Reproductive Sciences, Vol. 23, No. 4, 01.04.2016, p. 464-474.

Research output: Contribution to journalArticle

Abdelaziz, M, Sherif, L, Elkhiary, M, Nair, S, Shalaby, S, Mohamed, S, Eziba, N, El-Lakany, M, Curiel, D, Ismail, N, Diamond, MP & Al-Hendy, A 2016, 'Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for in Vivo Gene Therapy of Uterine Leiomyoma', Reproductive Sciences, vol. 23, no. 4, pp. 464-474. https://doi.org/10.1177/1933719116630413
Abdelaziz, Mohamed ; Sherif, Lotfy ; Elkhiary, Mostafa ; Nair, Sanjeeta ; Shalaby, Shahinaz ; Mohamed, Sara ; Eziba, Noura ; El-Lakany, Mohamed ; Curiel, David ; Ismail, Nahed ; Diamond, Michael Peter ; Al-Hendy, Ayman. / Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for in Vivo Gene Therapy of Uterine Leiomyoma. In: Reproductive Sciences. 2016 ; Vol. 23, No. 4. pp. 464-474.
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abstract = "Background: Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. Study design: An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Materials and methods: Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR. Results: In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P < 0.05), reduced expression of proliferation marker (PCNA) (P < 0.05), induced expression of apoptotic protein, c-PARP-1, (P < 0.05) and inhibited expression of extracellular matrix-related genes (TGF beta 3) and angiogenesis-related genes (VEGF & IGF-1) (P < 0.01). There were no detectable adenovirus in tested tissues other than leiomyoma lesions with both targeted and untargeted adenovirus. Conclusion: Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial.",
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AU - Nair, Sanjeeta

AU - Shalaby, Shahinaz

AU - Mohamed, Sara

AU - Eziba, Noura

AU - El-Lakany, Mohamed

AU - Curiel, David

AU - Ismail, Nahed

AU - Diamond, Michael Peter

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