Optimal modes and targets of gene therapy in transplantation

Abstract

Genetic modification strategies have the potential to improve outcome following cell/organ transplantation. A unique opportunity in transplantation is that gene therapies need not be restricted to in vivo approaches and that ex vivo genetic modification of cell and/or organs can be of value. Improvements in vector design, production, and delivery should enhance transfection efficiency and optimize gene expression. Herein, we discuss potential modes of gene therapy, focusing on viral, liposome, or naked DNA-based systems for gene delivery. We suggest gene therapy targets taking into consideration the essential constituents of anti-allograft repertory. In addition to strategies that may have salutary effects in mitigating the threat of acute rejection, we suggest genetic strategies for minimizing ischemia/reperfusion injury as well as for the perennial problem of progressive functional loss of the transplanted organ. Data from pre-clinical transplant models support the idea that gene therapy may improve allograft function and survival. We are optimistic that gene therapy will be of clinical value in the near future in the management of recipients of allografts; we believe that genetic strategies would be essential for successful breaching of the formidable challenge of xenotransplantation.

Strategies for Gene Transfer to Vascularized Composite Allografts

“…Having developed successful transplant models, clinicians and researchers in transplant immunology now have the opportunity to orient these applications toward preventing acute rejection, minimizing ischemia/reperfusion, toxicities associated with chronic immune suppression, and those features associated with progressive functional loss of the transplanted organ [4]. When selecting from among the wide array of vectors available, the features of each delivery system must be carefully weighed.…”

“…The details vary greatly in the type and size of payload, the affinity for certain target cells and tissues, and efficiency and safety profiles. According to an in-depth review on the evolving field of gene manipulation, there is a relatively standard and vital set of factors that one must take into consideration when selecting both the transfer vector and cellular target within applications of gene delivery technology [4][5][6]. Some of these considerations are summarized in the table below (Table 18.1).…”

“…Until recently, gene therapy delivery agents were classified into two basic categories which were defined as (1) viral agent vectors and (2) nonviral vectors. Those gene transfer means which operated within viral delivery constructs employed the use of adenoviruses, oncoretroviruses, lentiviruses, and adeno-associated viruses or AAVs [4,6]. Although evolutionarily adept at the Table 18.1 Desired feature of delivery system and description of feature.…”

“…Basic physical or nonchemical methods encompass electroporation, micro-fluid platforms cell squeezing, and sonoporation. New advances in electroporation as well as gene administration techniques have increased naked DNA transfection efficiencies [4,8].…”

“…Intravascular delivery of DNA into mice and nonhuman primates has been demonstrated to result in increased transgene delivery to kidney and muscle cells of up to 50 % [4,9]. The use of electroporation produces a tenfold increase in intramuscular DNA delivery gene expression.…”