Current Gene Therapy - Volume 8, Issue 1, 2008

Highly active antiretroviral therapy is not sufficient to fully control HIV replication and problems of side effects and escape mutation have emerged. Current prophylactic and therapeutic vaccine strategies appear to be unable to confer full protection. However, given the rapid recent progress made in RNA interference and lentivirus technologies, it may soon be possible to develop effective gene therapies against HIV infection. We describe here the recent progress made in the lentivirus-based HIV-1-targeting RNAi system and the possibility that this system can be used to generate an anti-HIV-1 gene therapy. We speculate that this system would be most useful if it would be used in a coordinated manner with vaccines that can initiate and maintain potent anti-HIV immunity.

Gemini surfactants provide a significant opportunity in the development of new non-viral delivery systems designed for gene therapy applications. This review summarizes the wide range of gemini surfactant structures that have been employed for DNA transfection in vitro. A general observation is that those structures capable of inducing a wide variety of polymorphic structures (lamellar, hexagonal, or cubic phases) demonstrate higher transfection efficiencies. Those compounds whose structures result in pH-dependent changes in aggregate structure similarly show higher levels of transfection. In vivo transfection using gemini surfactants has been demonstrated in only three cases, and in a recent study the transfection was linked to a specific therapeutic response.

The treatment of rheumatoid arthritis (RA) in the last decade has made enormous advances with the use of biological therapies. However, these therapies have serious limitations such as the expense, side-effects, and the requirement for repeated injections, each of which can potentially be obviated by gene therapy. A gene therapy approach for the treatment of RA has the potential to stably deliver a gene product or multiple products in a target-specific, disease-inducible manner. There are many studies investigating gene therapy in RA, the majority of which have been designed to test proofof- principle in an animal model. With an abundance of animal studies that have established much promise, the field is now at the early stage of moving towards human trials, where patient benefit needs to overshadow associated risks, especially since RA is publicly perceived as a non-life-threatening disease. Here, we provide an overview that focuses on advances in the application of gene therapy to RA over the last five years, including: novel targets and approaches; the viral and non-viral applications most likely to succeed in the clinic; advances in our understanding of the contralateral effect; the latest successes with anti-inflammatory cytokines; and a review of advancements towards clinical trials.

Chronic pain is a highly prevalent condition that impacts adversely on individual quality of life, imposes substantial costs on the healthcare system and a considerable burden on society. Advances in the understanding of pain mechanisms have opened the way for the development of new treatment strategies. The continuous delivery of short-lived potent bioactive molecules to sensory nerves, spinal cord or meninges - achieved by directed gene transfer - offers the possibility to selectively interrupt nociceptive neurotransmission or to interfere with the plastic changes in the nervous system underlying the development or persistence of chronic pain. In this review we describe advances in the use of nonviral and viral vector-based gene transfer for the treatment of pain, with a special focus on the use of recombinant nonreplicating herpes simplex virus-based vectors and the prospects for clinical trials.

The aim of the present article is to discuss the potential of gene therapy for thymic hormones as a novel therapeutic strategy to treat dyshomeostatic conditions associated with congenital athymia or hypofunction of the endocrine thymus. Recent studies using an adenoviral vector harboring a synthetic gene for the thymic peptide thymulin are reviewed. This adenoviral vector was injected intramuscularly in thymectomized and nude mice as well as in thymectomized rats. Transduced myocytes acted as an ectopic source of thymulin thus restoring circulating thymulin levels to normal values. This restorative effect was long lasting (several months) even though an adenoviral vector was used. In the rat brain, adenovirally-mediated delivery of the synthetic gene for thymulin achieved longer expression than in the case of adenovirally-delivered reporter genes, which is consistent with the reported antiinflammatory activity of thymulin in the brain. Furthermore, neonatal thymulin gene therapy in nude female mice was able to prevent the pituitary and ovarian alterations that typically occur in this mutant after puberty. Neonatal thymulin gene therapy in nude mice was able to prevent some of the alterations in lipid metabolism that develop during adult life in congenitally athymic mice. We conclude that the availability of the above biotechnological tools should boost basic studies on the molecular biology of thymulin and should also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models and eventually, in humans.

Baculovirus has emerged as a novel vector for in vivo and in vitro gene delivery. In addition, the applications of baculovirus-mediated gene transfer have been explosively expanded to drug screening, eucaryotic gene display, cancer therapy and tissue engineering, etc. The capability of baculovirus viral envelope for protein/peptide display also renders itself a potential vaccine delivery platform. This paper reviews the history, factors influencing baculovirus-mediated gene delivery and emerging in vitro, in vivo and ex vivo applications. Efforts aimed at overcoming current existing bottlenecks and recent progresses in addressing the safety concerns are particularly emphasized.