Current Gene Therapy (v.13, #1)

Preface by Ignacio Anegon (1-1).

In-Vivo Gene Delivery by Sonoporation: Recent Progress and Prospects by Jean-Michel Escoffre, Aya Zeghimi, Anthony Novell, Ayache Bouakaz (2-14).
The increasing knowledge of cellular and molecular mechanisms of human diseases allows envisaging the gene therapy by sonoporation as an emerging and promising therapeutic alternative. Sonoporation combines the local application of ultrasound waves and the intravascular or intratissue administration of gas microbubbles. In such a way, the permeability of vessels and tissues to the poorly permeant molecules is transiently increased. Ultrasound based modality offers new opportunities since ultrasound can be easily focused on a target tissue or organ and hence gene delivery and expression should be limited to the insonified region. Consequently, it might be possible to develop an efficient and safe tissue- or organ-specific delivery method by microbubble targeting and focused ultrasound. This review focuses on the current knowledge of sonoporation fundamentals and mechanisms. The sonoporation procedure and current preclinical trials will be then presented. Finally, the new challenges of sonoporation will be discussed.

Interleukin-15 in Gene Therapy of Cancer by Maria C. Ochoa, Guillermo Mazzolini, Sandra Hervas-Stubbs, Miguel F. de Sanmamed, Pedro Berraondo, Ignacio Melero (15-30).
Interleukin-15 (IL-15) exerts powerful stimulatory effects on lymphocyte subsets that result in antiviral and antitumoral activities. The functions of this cytokine are mainly mediated in a cell-to-cell contact fashion termed IL-15 trans-presentation. This function is mediated by a cell which tethers IL-15 to its plasmatic membrane complexed to IL-15 receptor alpha (IL-15Rα). Such surface complexes interact with interleukin-2 receptor beta and gamma on the adjacent cell to elicit signaling. Unlike interleukin-2, IL-15 protects from activation-induced cell death and does not promote regulatory cells. These features underlie its activity against transplanted tumors and its adjuvanticity in tumor and viral vaccines. The GMP-manufactured recombinant protein is undergoing clinical trials but its rapid renal clearance calls for biotechnological strategies to increase molecular weight and ensure IL-15Rα. trans-presentation. Since early efforts with stable transfected tumor cells, IL-15 has been tested in a variety gene therapy approaches. Those mainly include transfer of expression cassettes to tumor cells, T cells, dendritic cells, vaccination sites and the liver as a biofactory organ. Detailed mechanistic knowledge of IL-15 biology is envisaged to make the most of a powerful immunotherapeutic tool ranked as one of the most promising for cancer immunotherapy.

Transendocardial Delivery of HGF Via Microbubbles and Ultrasound to Treat Acute Myocardial Infarction by Qiao-Ying Yuan, Jing Huang, Xue-Jun Li, Xing-Sheng Li, Liang-Yi Si (31-38).
To enhance the safety of transendocardial delivery and the efficacy of intramyocardial angiogenic gene expression, a visible, less invasive, targeted, high-efficiency gene delivery strategy was tested. Progress toward clinical approval of systemic administration of genes and microbubbles (MBs) has been limited. The feasibility of transendocardially delivering MBs as extracellular markers and gene carriers in conjunction with intracardiac ultrasound (US) treatment remains unknown. In a canine acute myocardial infarction (MI) model, a naked plasmid encoding 500 &#x3BC;g human hepatocyte growth factor (HGF) was delivered transendocardially to the myocardium via US/MB (HGF-US/MB), insonation (HGFUS), or alone (HGF alone). Control MI dogs received saline without US/MB (control group). During US/MB, intracardiac insonation was performed for 30 s with a 10-s pause, at 4.3-MHz, 1-W/cm2, for 60 s at each site. Gene and MB distribution in the myocardium was visualized. Compared to the HGF alone group at 28 days, the HGF-US/MB group had an average 7.1-fold enhancement in gene expression (P < 0.01). Compared to the control group, there were 16% decreases in the ratio of left ventricle (LV) weight/body weight in the HGF-US/MB group and decreases in collagen volume fraction (CVF) of type I (33%) and type III (23%) collagen. Capillary density increased from 22.8 ± 6.3/mm2 in the control group to 154.3 ± 42.9/mm2 in the HGF-US/MB group (P < 0.01). This less invasive catheter-based US therapeutic procedure offers observable gene delivery with higher therapeutic efficiency, enhanced angiogenesis, and improved myocardial perfusion and ventricular function following MI.

Methamphetamine is a highly addictive psychostimulant that has been seriously abused worldwide, and currently there are no approved medications for the treatment of its abuse. Conventional treatments for drug addiction mainly seek to use small molecule agonists or antagonists to target the drug receptors in the brain, but unfortunately it is difficult to find a similar small molecule for the treatment of methamphetamine dependence. Alternatively, anti-methamphetamine antibodies can sequester the drug in the bloodstream and reduce the amount of drug available to the central nervous system, acting as peripheral pharmacokinetic antagonists. This review describes the development of antibody-based immunotherapies, classified into active and passive immunizations, for the treatment of methamphetamine addiction. Furthermore, an alternative therapeutic approach, using a recombinant adeno-associated virus-mediated gene transfer technique to achieve in vivo expression of characterized anti-methamphetamine monoclonal antibodies, is proposed in this article.

Gene Elements that Regulate Streptococcus pneumoniae Virulence and Immunity Evasion by Pamela A. Nieto, Sebastian A. Riquelme, Claudia A. Riedel, Alexis M. Kalergis, Susan M. Bueno (51-64).
Streptococcus pneumoniae is one of the most important aetiological agents of bacterial pneumonia and meningitis in the world. This bacterium can cause severe inflammation of lung tissue and disseminate to the central nervous system. Although B cell activation and antibody secretion is considered one of the most important events in the prevention or clearance of bacterial infection by the host, dendritic cells (DCs) and T cells play a fundamental role in the generation of the protective immunity required to prevent the pathogenesis caused by S. pneumoniae infection. Here we review recent studies that have evaluated the impact of DCs and T cells on S. pneumoniae infection and the gene elements encoding virulence factors used by this bacterium to interfere with the appropriate function of these immune cells. This knowledge could be relevant for generating new prophylactic and therapeutic tools and to prevent the severe infection caused by this pathogen.

Strategies to Improve the Clinical Performance of Chimeric Antigen Receptor-Modified T Cells for Cancer by Qing Zhang, Huizhong Li, Jie Yang, Liantao Li, Baofu Zhang, Jia Li, Junnian Zheng (65-70).
Clinical trials of chimeric antigen receptor (CAR)-modified T cells have shown promise in hematologic malignancies. However, in solid tumors, the clinical responses have been less impressive. It is important to determine how to further improve the clinical effects of CAR-modified T cells. In this review, we focus on recent clinical trials and analyze the factors that determine clinical responses, including the following: 1) the composition of the CAR; 2) the preparation of CAR-modified T Cells; 3) the clinical treatment schedule; 4) the patient characteristics. We also propose future Strategies that must be investigated before the technology can be used in a wider range of clinical applications.