Disease Targets

Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS) [1]. According to the report from World Health Organization (WHO), in 2009, there were 33.3 million people living with HIV/AIDS, with 2.6 million new infections and 1.8 million deaths due to AIDS (http://www.who.int/hiv/data/2009_global_summary.png). HIV infection affects a large area and spreads actively ever since it was identified, with a significant number of AIDS deaths occurring in Sub-Saharan Africa [Greener R (2002) AIDS and macroeconomic impact. In S, Forsyth (ed) State of the Art: AIDS and Economics IAEN: pp. 49-55].

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder with an incidence rate of 1:80,000 births in Japan (1). It occurs when a mutant enzyme protein (OTC) impairs the reaction that leads to condensation of carbamoyl phosphate and ornithine to form citrulline. This impairment leads to reduced ammonia incorporation, which, in turn, causes hyperammonemia. Ammonia is especially damaging to the nervous system, so ornithine transcarbamylase deficiency causes neurological problems as well as eventual damage to the liver.

PKU is an autosomal recessive disorder resulting from a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine (figure 1) (1). PAH deficiency is the most common cause of the accumulation of phenylalanine (Phe), called hyperphenylalanemia (HPA), with an incidence of roughly 1:10000 Caucasian live births, with a higher incidence in the populations of Turkey, Ireland and Norway (http://emedicine.medscape.com/article/947781-overview).

A number of different enzymes and molecules are involved in the maintenance of reduction-oxidation reaction (redox) balance in tissues. The three mammalian dismutases, cytosolic CuZnSOD (SOD1), mitochondrial MnSOD (SOD2), and extracellular superoxide dismutase (SOD3) are among the most important redox enzymes. They differ by the cellular localization and therefore have slightly different regulation of expression and therapeutic effects in tissue damage recovery suggesting distinct targets for gene therapy. In the current review I focus on the regulation of SOD3 gene expression in tissues and on the effect of SOD3 transgene on signal transduction.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in American males today. Novel and effective treatment such as gene therapy is greatly desired. Gene therapy is the direct transfer of DNA into patients’ diseased cells for the purpose of therapy. Viral based gene therapy is to use a genetically-modified, replication defective or so-called cold virus as the gene transfer vehicle. In contrast, nonviral gene therapy is to deliver DNA by nonviral methods. At the current stage, viral gene therapy in general has a much higher gene transfer efficiency in vivo compared to nonviral gene therapy. The early viral-based gene therapy uses tissue-nonspecific promoters, which causes unintended toxicity to other normal tissues. In this mini-review, we will focus on discussion of strategy using transcriptionally-regulated gene therapy strategy for prostate cancer treatment.

A recent article published on the New England Journal of medicine by Aiuti and colleagues reports on the progress of 10 patients that have been treated for ADA-SCID by gene therapy. This is a form of severe combined immuno-deficiency (SCID) where there is a lack of the enzyme adenosine deaminase (ADA), coded for by a gene on chromosome 20.

Mesothelioma is relatively rare in frequency but is one of the intractable cancers linked with asbestos exposure. The patient numbers will increase in near future and current clinical outcomes with conventional treatment modalities are not satisfactory. Gene therapy is a possible therapeutic strategy because of easy accessibility of a vector system into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced anti-tumor effects, suggesting the clinical feasibility. In this review, we summarized the current status of clinical trials targeting mesothelioma.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by the absence of dystrophin in the muscle. This large protein of 427 kDa is encoded by a 14 kb mRNA (79 exons) (1). This dystrophin protein is located under the membrane of the muscle fiber and interacts with other trans-membrane proteins. It is needed to insure mechanical stress resistance during muscle contraction. The lack of dystrophin weakens the sarcolemma and thus makes fibers less resistant to stress. When a fiber is damaged, the satellite cells (stem cells located near the muscle fibers) are activated and proliferate to allow fiber regeneration (2). In the case of a DMD patient, fibers are frequently damaged due to the lack of dystrophin. The regeneration is also ensured by the proliferation of satellite cells though their number decreases rapidly and when there are no more satellite cells, the average diameter and the number of fibers progressively decrease bringing the development of fibrosis and fat infiltrations into the muscles. There is currently no treatment for DMD and life expectancy is between 20 to 25 years of age.

Prolonged ischemic insult can cause irreversible tissue injuries. Despite advances in medical and surgical therapies, myocardial infarction and stroke, both consequences of ischemic insults, remain to be the top two causes of morbidity and mortality in the Western world, with survivals usually carrying permanent disabilities. Treatments that help restoring blood flow to ischemic area remain to be one of the most important therapeutic goals. Enhancing the innate angiogenesis by exogenous delivery of angiogenic factors lessens the ischemic injury. However, uncontrolled angiogenic gene expression can cause some unwanted side effects. In this mini-review, we describe two systems that can be used to mediate hypoxia-inducible and tissue-specific gene expression.

Replication-defective adenoviruses are widely used as gene transfer vectors to deliver cytostatic or tumour suppressor genes into a variety of cancers, yielding some of the most promising results in the clinic. Indeed, the most successful adenoviral vectors used to date are those that are designed to deliver p53 into tumours. Tumor cells have lost the function of p53 because of mutations in the DNA-binding region of the molecule, a feature that is present in over 50% of all human malignancies. A number of studies have demonstrated that transfer of wild type (wt) p53 gene is able to suppress tumor cell proliferation. Moreover, platinum-based chemotherapy enhances mutations in the p53 in the heterogenous cell population; transfer of the wild type p53 gene enhanced the sensitivity of chemoresistant cells to cisplatin and cisplatin-induced apoptosis (Kigawa et al, 2002). This has led to a significant amount of clinical trials where wt p53 has been re-introduced to tumour cells by the use of first-generation adenoviral vectors.