Astrocytes as Cellular Vehicles in Ex Vivo Gene Therapy Studies to the Rat Brain

Cecilia Ericson

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Neurodegenerative disorders are characterized by a progressive cell-death in the brain, and loss of different functions in the patient. Today, there are no cures for any of the various diseases. Parkinson's disease is a neurodegenerative disorder with a prevalence of 0.1% and the first symptoms usually start to appear between 50-60 years of age with rigidity, tremor, bradykinesia and postural abnormalities. Even though the reason for the development is not fully understood, the pathophysiology of the disease has been well documented. ?Sere is a progressive loss of dopamine-producing cells in substantia nigra in the midbrain, resulting in a significant decline of dopamine levels in the striatum and a disturbed motoric function. ?Se most common treatment today is oral intake of levodopa, the rate-limiting enzyme in the dopamine synthesis pathway, however the effects of the drug becomes limited over time and hence, there is a need for alternative therapy. Instead of using fetal human tissue for transplantation, with both logistical and ethical dilemmas, ex vivo gene therapy holds great promise for treatment of different neurodegenerative disorders. Ex vivo gene therapy is a combination of cell transplantation and genetic engineering, with the aim of restoring lost neurotransmitters, such as dopamine, or to transfer neurotrophic factors to stimulate cell survival in a damaged or injured brain. In the present thesis, I have genetically modified primary astrocytes of both rodent and human origin with lentiviral vectors in order to evaluate the potential of the cells to provide long-term transgene expression following transplantation to the rat brain. Astrocytes are a type of glial cells in the brain attributed various functions, and have been explored in several studies to be used as cellular vehicles in ex vivo gene delivery to the central nervous system. Compared to previous studies were astrocytes have been genetically modified in vitro using other viralbased vectors, I have shown in my work that lentivirally transduced astrocytes have the capacity to express the transgene product at significant levels for up to at least 12 weeks after grafting to the rat brain. However, before moving towards clinical trials using genetically modified astrocytes, the vector system has to be further developed in order to be able to regulate the transgene expression, even after the cells have been integrated within the host brain.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Lundberg, Cecilia, Supervisor
Award date2005 Apr 16
Publisher
Print ISBNs91-85439-17-7
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-04-16
Time: 09:15
Place: Segerfalksalen, Wallenberg Neurocentrum. Lund

External reviewer(s)

Name: Barker, Roger
Title: Dr
Affiliation: University of Cambridge, UK

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<div class="article_info">Cecilia Eriksson, Cecilia Ericson, Monte A. Gates and Klas Wictorin. <span class="article_issue_date">2000</span>. <span class="article_title">Long-term, EGF-stimulated cultures of attached GFAP-positive cells derived from the embryonic mouse lateral ganglionic eminence: in vitro and transplantation studies.</span> <span class="journal_series_title">Exp Neurol.</span>, <span class="journal_volume">vol 164</span> <span class="journal_pages">pp 184-99</span>.</div>
<div class="article_info">Ulrica Englund, Cecilia Ericson, Carl Rosenblad, Ron J. Mandel, Didier Trono, Anders Björklund, Klas Wictorin and Cecilia Lundberg. <span class="article_issue_date">2000</span>. <span class="article_title">The use of a recombinant lentiviral vector for ex vivo gene transfer into the rat CNS.</span> <span class="journal_series_title">NeuroReport</span>, <span class="journal_volume">vol 11</span> <span class="journal_pages">pp 3973-7</span>.</div>
<div class="article_info">Cecilia Ericson, Klas Wictorin and Cecilia Lundberg. <span class="article_issue_date">2002</span>. <span class="article_title">Ex vivo and in vitro studies of transgene expression in rat astrocytes transduced with lentiviral vectors.</span> <span class="journal_series_title">Exp Neurol.</span>, <span class="journal_volume">vol 173</span> <span class="journal_pages">pp 22-30</span>.</div>
<div class="article_info">Cecilia Ericson, Biljana Georgievska* and Cecilia Lundberg*. <span class="article_issue_date"></span>. <span class="article_title">Long-term ex vivo gene delivery of GDNF using primary astrocytes transduced with a lentiviral vector provides neuroprotection in a rat model of Parkinson’s disease.</span> (submitted)</div>
<div class="article_info">Cecilia Ericson, Nina Rosenqvist, Marie Jönsson, Bengt Juliusson, Philip Kusk, Teit E. Johansen and Cecilia Lundberg. <span class="article_issue_date"></span>. <span class="article_title">Ex vivo gene delivery to the rat brain using human astrocytes transduced with a lentiviral vector.</span> (manuscript)</div>

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • Medicin (människa och djur)
  • Medicine (human and vertebrates)
  • Lentivirus
  • Transplantation
  • CNS
  • Astrocytes

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