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Tandem Delivery of Multiple Therapeutic Genes Using Umbilical Cord Blood Cells Improves Symptomatic Outcomes in ALS

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Abstract

Current treatment options of chronic, progressive degenerative neuropsychiatric conditions offer only marginal efficacy, and there is no therapy which arrests or even reverses these diseases. Interest in genetic engineering and cell-based approaches have constantly been increasing, although most of them so far proved to be fruitless or at best provided very slight clinical benefit. In the light of the highly complex patho-mechanisms of these maladies, the failure of drugs aimed at targeting single molecules is not surprising. In order to improve their effectiveness, the role of a unique triple-combination gene therapy was investigated in this study. Intravenous injection of human umbilical cord blood mononuclear cell (hUCBMC) cotransduced with adenoviral vectors expressing vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) resulted in prominent increase of life span and performance in behavioral tests in amyotrophic lateral sclerosis (ALS). Expression of the recombinant genes in hUCBMCs was confirmed as soon as 5 days after transduction by RT-PCR, and cells were detectable for as long as 1 month after grafting in lumbar spinal cord by immunofluorescent staining. Xenotransplantation of cells into mice blood without any immunosuppression demonstrated a high level of hUCBMCs homing and survivability in the central nervous system (CNS), most conspicuously in the spinal cord, but not in the spleen or liver. This study confirms an increased addressed homing and notable survivability of triple-transfected cells in lumbar spinal cord, yielding a remarkably enhanced therapeutic potential of hUCBMCs overexpressing neurotrophic factors.

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Acknowledgments

This study was supported by the grant of Russian Science Foundation no. 16-15-00010. The work is performed according to the Russian Government Program of Competitive Growth of Kazan Federal University and subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities. Some of the experiments were conducted using the equipment of interdisciplinary center for collective use of Kazan Federal University supported by Ministry of Education of Russia (ID RFMEFI59414X0003), Interdisciplinary Center for Analytical Microscopy and Pharmaceutical Research and Education Center, Kazan (Volga Region) Federal University, Kazan, Russia.

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Authors and Affiliations

  1. Kazan State Medical University, Kazan, Russia

    Rustem Robertovich Islamov, Andrey Alexandrovich Izmailov, Ekaterina Evgenyevna Garanina, Mikhail Evgenyevich Sokolov & Marat Alexandrovich Mukhamedyarov

  2. Department of Biology, Kazan State Medical University, ul. Butlerova 49, R-420012, Kazan, Russia

    Rustem Robertovich Islamov

  3. Kazan Federal University, Kazan, Russia

    Albert Anatolyevich Rizvanov, Valeria Yuryevna Fedotova, Zufar Zufarovich Safiullov, Ilnur Ildusovich Salafutdinov & András Palotás

  4. Asklepios-Med (private medical practice and research center), Kossuth Lajos sgt. 23, Szeged, H-6722, Hungary

    András Palotás

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  1. Rustem Robertovich Islamov
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  2. Albert Anatolyevich Rizvanov
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  3. Valeria Yuryevna Fedotova
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  4. Andrey Alexandrovich Izmailov
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  5. Zufar Zufarovich Safiullov
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  6. Ekaterina Evgenyevna Garanina
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  7. Ilnur Ildusovich Salafutdinov
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  8. Mikhail Evgenyevich Sokolov
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  9. Marat Alexandrovich Mukhamedyarov
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  10. András Palotás
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Correspondence to Rustem Robertovich Islamov or András Palotás.

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Islamov, R.R., Rizvanov, A.A., Fedotova, V.Y. et al. Tandem Delivery of Multiple Therapeutic Genes Using Umbilical Cord Blood Cells Improves Symptomatic Outcomes in ALS. Mol Neurobiol 54, 4756–4763 (2017). https://doi.org/10.1007/s12035-016-0017-x

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  • DOI: https://doi.org/10.1007/s12035-016-0017-x

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