Current Gene Therapy

ISSN: 1566-5232

Current Gene Therapy
Volume 7, Number 4, August 2007

Contents


Adenovirus Vectors Composed of Subgroup B Adenoviruses Pp. 229-238
Fuminori Sakurai, Kenji Kawabata and Hiroyuki Mizuguchi
[Abstract]


Gene Therapy for Peripheral Nervous System Diseases Pp. 239-248
Thais Federici and Nicholas Boulis
[Abstract]


Genetically Engineered Stem Cells for Therapeutic Gene Delivery Pp. 249-260
Claudius Conrad, Rashmi Gupta, Hema Mohan, Hanno Niess, Christiane J. Bruns, Reinhard Kopp, Irene von Luettichau, Markus Guba, Christopher Heeschen, Karl-Walter Jauch, Ralf Huss and Peter J. Nelson
[Abstract]


Foamy Virus Vectors: An Awaited Alternative to Gammaretro- and Lentiviral Vectors Pp. 261-271
Axel Rethwilm
[Abstract]


Emerging Adenoviral Vectors for Stable Correction of Genetic Disorders Pp. 272-283
Lorenz Jager and Anja Ehrhardt
[Abstract]


Potential Application of Gene Therapy to X-Linked Agammaglobulinemia Pp. 284-294
Thomas Moreau, Boris Calmels, Vincent Barlogis, Gérard Michel, Cécile Tonnelle and Christian Chabannon
[Abstract]




Abstracts


[Back to top]
Adenovirus Vectors Composed of Subgroup B Adenoviruses
Fuminori Sakurai, Kenji Kawabata and Hiroyuki Mizuguchi

Recombinant adenovirus (Ad) vectors have gained attention as gene delivery vehicles because they efficiently introduce foreign DNA into host cells, can be produced in high titers, and are able to transduce terminally differentiated cells. Conventional Ad vectors commonly used in the world, including clinical trials, are derived from subgroup C Ad serotype 5 (Ad5). Although Ad5 vector-mediated transduction provides encouraging results, preclinical and clinical applications have revealed several disadvantages of Ad5 vectors, such as high seroprevalence of anti-Ad5 antibodies in adults and low transduction efficiencies of Ad5 vectors in cells lacking the primary receptor for Ad5, the coxsackievirus and adenovirus receptor (CAR). To overcome these problems, novel recombinant Ad vectors, which are derived entirely from subgroup B Ads, including Ad serotypes 3, 7, 11, and 35, have been developed. These subgroup B Ad vectors can infect cells via human CD46 (membrane complement protein), which is ubiquitously expressed in almost all human cells, and/or via unidentified receptors other than CAR, leading to efficient transduction of subgroup B Ad vectors in most human cells, including CAR-negative cells. In addition, transduction efficiencies of subgroup B Ad vectors do not decrease in the presence of anti-Ad5 antibodies, and seroprevalences of most subgroup B Ads are lower than that of Ad5, indicating that transduction with subgroup B Ad vectors is unlikely to be hampered by preexisting anti-Ad antibodies. In this paper, we review the advances in subgroup B Ad vector research.


[Back to top]
Gene Therapy for Peripheral Nervous System Diseases
Thais Federici and Nicholas Boulis

Peripheral nerve diseases, also known as peripheral neuropathies, affect 15-20 million of Americans and diabetic neuropathy is the most common condition. Currently, the treatment of peripheral neuropathies is more focused on managing pain rather than providing permissive conditions for regeneration. Despite advances in microsurgical techniques, including nerve grafting and reanastomosis, axonal regeneration after peripheral nerve injury remains suboptimal. Also, no satisfactory treatments are available at this time for peripheral neurodegeneration occurring in motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Peripheral nerves have the inherent capacity of regeneration. Gene therapy strategies focused on neuroprotection may help optimizing axonal re-growth. A better understanding of the cellular and molecular events involved in axonal degeneration and regeneration have helped researchers to identify targets for intervention. This review summarizes the current state on the clinical experience as well as gene therapy strategies for peripheral neuropathies, including MND, peripheral nerve injury, neuropathic pain, and diabetic neuropathy.


[Back to top]
Genetically Engineered Stem Cells for Therapeutic Gene Delivery
Claudius Conrad, Rashmi Gupta, Hema Mohan, Hanno Niess, Christiane J. Bruns, Reinhard Kopp, Irene von Luettichau, Markus Guba, Christopher Heeschen, Karl-Walter Jauch, Ralf Huss and Peter J. Nelson

Stem cell and gene therapy approaches have held out much hope for the development of new tools to treat disease. Therapeutic approaches based on these methods have only rarely found their way into the clinic. The linking of stem cell therapy with selective gene therapy enhances therapeutic options for the regeneration or replacement of diseased or missing cells. This review focuses on the rationale and preliminary results of combining stem cell and gene therapy. Special emphasis is placed on various molecular techniques currently used to genetically engineer stem cells. Viral and non-viral genes delivering technologies are detailed as are techniques for the modulation of gene expression in the context of stem cell recruitment and differentiation. Finally potential clinical applications for this new therapeutic strategy are discussed.


[Back to top]
Foamy Virus Vectors: An Awaited Alternative to Gammaretro- and Lentiviral Vectors
Axel Rethwilm

The first vectors derived from foamy viruses were established over ten years ago. Until now only used and further developed by a handful of investigators these vectors have been shown to be promising tools for the gene transfer into haematopoietic stem cells. Several inherent features of foamy virus-derived vectors, such as the high efficiency in targeting CD34-positive stem cells, a favourable integration profile, and the apathogenic nature of the parental virus, indicate that they are superior to gammaretroviral and lentiviral vectors. The effectiveness in different preclinical animal models suggests the exploration of foamy virus vectors in human trials.


[Back to top]
Emerging Adenoviral Vectors for Stable Correction of Genetic Disorders
Lorenz Jager and Anja Ehrhardt

Recent drawbacks in treating patients with severe combined immunodeficiency disorders with retroviral vectors underline the importance of generating novel tools for stable transduction of mammalian cells. Substantial progress has been made over the recent years which may offer important steps towards stable and more importantly safer correction of genetic diseases. This article discusses recent advances for stable transduction of target cells based on adenoviral gene transfer. There is accumulating evidence that recombinant adenoviral vectors (AdVs) based on various human serotypes with a broad cellular tropism and adenoviruses (Ads) from different species will play an important role in future gene therapy applications. In combination with recombinant AdVs for somatic integration these gene transfer vectors offer high transduction efficiencies with potentially safer integration patterns. Other approaches for persistent transgene expression include excision of stable episomes from the adenoviral vector genome, but also long-term persistence of the complete adenoviral vector genome as an episomal DNA molecule was demonstrated and exemplified by the treatment of various genetic diseases in small and large animal models. This review displays advantages but also limitations of these Ad based vector systems. This is the perfect time to pursue such approaches because alternative strategies for stable transduction of mammalian cells undergoing many cell divisions are urgently needed. Looking into the future, we believe that a combina-tion of different components from different viral vectors in concert with non-viral vector systems will be successful in designing significantly optimized transfer vehicles for a broad range of different genetic diseases.


[Back to top]
Potential Application of Gene Therapy to X-Linked Agammaglobulinemia
Thomas Moreau, Boris Calmels, Vincent Barlogis, Gérard Michel, Cécile Tonnelle and Christian Chabannon

X-linked agammaglobulinemia (XLA), or Bruton’s disease, is the most common human primary humoral immunodeficiency. XLA is caused by mutations of the Bruton’s tyrosine kinase (BTK), a key regulator of B-cell physiology. Since the mid 80’s, substitutive therapy by intravenous gammaglobulin infusions has significantly improved XLA patient survival and quality of life. Nevertheless, some frequent affections persist despite treatment, and lead to handicapping and further to morbid clinical complications for XLA individuals. Development of gene therapy by transfer of the BTK gene into hematopoietic progenitors could represent an alternative strategy for the treatment of Bruton’s disease, with the advantage of a definitive cure for XLA patients. Gene therapy of XLA could be considered as a paradigm for future expansion of gene therapy approaches for many other diseases, since future utilization may be strictly dependent on a marked improvement of risk-benefit ratio compared to pre-existing treatments.