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Therapeutic Technology and Methodology / Therapy / Gene Therapy

State-Of-The-Art Human Gene Therapy: Part I. Gene Delivery Technologies

Abstract: Safe and effective gene delivery is a prerequisite for successful gene therapy. In the early age of human gene therapy, setbacks due to problematic gene delivery vehicles plagued the exciting therapeutic outcome. However, gene delivery technologies rapidly evolved ever since. With the advancement of gene delivery techniques, gene therapy clinical trials surged during the past decade. As the first gene therapy product (Glybera) has obtained regulatory approval and reached clinic, human gene therapy finally realized the promise that genes can be medicines. The diverse gene delivery techniques available today have laid the foundation for gene therapy applications in treating a wide range of human diseases. Some of the most urgent unmet medical needs, such as cancer and pandemic infectious diseases, have been tackled by gene therapy strategies with promising results. Furthermore, combining gene transfer with other breakthroughs in biomedical research and novel biotechnologies opened new avenues for gene therapy. Such innovative therapeutic strategies are unthinkable until now, and are expected to be revolutionary. In part I of this review, we introduced recent development of non-viral and viral gene delivery technology platforms. As cell-based gene therapy blossomed, we also summarized the diverse types of cells and vectors employed in ex vivo gene transfer. Finally, challenges in current gene delivery technologies for human use were discussed. ... Read more

Gene Therapy for Obesity: Progress and Prospects

Abstract: Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. ... Read more

Current siRNA Targets in Atherosclerosis and Aortic Aneurysm

Abstract: Atherosclerosis (ATH) and aortic aneurysms (AA) remain challenging chronic diseases that confer high morbidity and mortality despite advances in medical, interventional, and surgical care. RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH and AA. Despite positive results in preclinical and some clinical feasibility studies, challenges such as target/sequence validation, tissue specificity, transfection efficiency, and mitigation of unwanted off-target effects remain to be addressed. In this review the most current targets and some novel approaches in siRNA delivery are being discussed. Due to the plethora of investigated targets, only studies published between 2010 and 2014 were included. ... Read more

Novel Approaches and Mechanisms in Hematopoietic Stem Cell Gene Therapy

Abstract: Hematopoietic stem cell gene therapy is one of the most exciting clinical tools to emerge from the gene therapy stable. This technology combines the expansion capability of hematopoietic stem cells, capable of replacing the entire blood and immune system of an individual, with the capacity for long-term replacement of one or more gene copies using integrating gene therapy vectors. Hematopoietic stem cell gene therapy benefits significantly from the pre-existing experience of standard blood and marrow transplantation, whilst at the same time having the capacity to deliver a safer and more effective therapy to a wider range of diseases. In this review we summarize the potential of hematopoietic stem cell gene therapy to expand the scope of hematopoietic stem cell transplantation, including the evolution of vector delivery systems and the success and failures of current clinical experience with this treatment. In particular we deal with the incidence of vector mediated transformation in patients and the steps that have been taken to minimize this risk. Finally we discuss the innovations in preclinical development that are likely to drive the future of this field, including the expansion to many more genetic diseases, particularly those affecting the brain. ... Read more

Combination of Virotherapy and T-cell Therapy: Arming Oncolytic Virus with T-cell Engagers

Abstract: While cure rates for several cancers have significantly improved, the outcome for patients with advanced solid tumors remains grimly unchanged over the last decades. Thus, there is a need for new therapies that could improve outcome for patients who fail current therapies. Oncolytic (cancer destroying) vaccinia virus (VV) would be an appealing addition to the current therapies of cancers because of its ability to infect, replicate in, and lyse tumor cells, and spread to other tumor cells in successive rounds of replication. While clinical studies have demonstrated their safety, the antitumor efficacy of oncolytic VVs has been suboptimal. Oncolytic VVs' major mode of action is the destruction of tumor cells, which can subsequently activate a component of the immune system called T-cells that can travel to distant sites and target against any tumor they find. At present, virus spread through tumors, as well as the activation of tumor-specific T-cells, is limited, explaining the observed suboptimal antitumor activity of current oncolytic VVs. Thus it would be desirable to make the oncolytic VVs more powerful stimulators of immunity through activating resident T-cells within the tumors so that they will kill tumor cells and stop new tumors from growing. To activate T-cells within tumors, a new molecule called a T-cell engager that couples the T cell and the tumor cell, which increases the effectiveness of the T cells and their activation, has been constructed. This review summarizes the progress of the emerging field of combinations of oncolytic virotherapy and T-cell based therapy. ... Read more

Humoral Immunity to AAV Vectors in Gene Therapy: Challenges and Potential Solutions

Abstract: Gene transfer trials with adeno-associated virus (AAV) vectors have initiated to unveil the therapeutic potential of this approach, with some of the most exciting results coming from clinical studies of gene transfer for hemophilia B, congenital blindness, and the recent market approval of the first AAV-based gene therapy in Europe. With clinical development, however, some of the limitations of in vivo gene transfer have emerged; in particular the host immune system represents an important obstacle to be overcome in terms of both safety and efficacy of gene transfer in vivo with AAV vectors. Results in humans undergoing gene transfer indicate that capsid-specific T cell responses directed against transduced cells may limit the duration of transgene expression following AAV gene transfer, and similarly anti-AAV neutralizing antibodies can completely prevent transduction of a target tissue, resulting in lack of efficacy. Anti-AAV neutralizing antibodies are highly prevalent in humans, and the frequency of subjects with detectable titers can reach up to two thirds of the population. The approach to the problem of preexisting humoral immunity to AAV so far has been the exclusion of seropositive subjects, but this solution is far from being optimal. Several additional strategies have been proposed and tested in a variety of preclinical animal models. Future studies will help defining the optimal strategy, or combination of strategies, to successfully treat subjects with preexisting antibodies to AAV due to natural infection or to prior administration of AAV vectors. These advancements will likely have a significant impact on the field of gene transfer with AAV vectors. ... Read more

Innovative Approaches for Enhancing Cancer Gene Therapy

Abstract: Gene therapy provides a novel platform for therapeutic intervention of several genetic and non-genetic disorders. With the recent developments in the field, a wide variety of viral and non-viral vectors have emerged that can deliver genetic payloads to target cells. However, non-targeted delivery of transgenes often results in undesirable effects, low tumor transduction, and reduced therapeutic index. In this review, we focus on some of the novel approaches that can be used to meet the present challenges in the field and translate the potential of cancer gene therapy from 'bench to bedside' in the near future. ... Read more

Novel Therapeutic Approaches for Corneal Disease

Abstract: Congenital and acquired corneal opacities, and diseases of the ocular surface, are blinding conditions that impose physical, psychological, and financial constraints upon the sufferer. In the past, corneal and corneal epithelial stem cell transplantation have been the major treatment for severe corneal and ocular surface disease, respectively, but the sequelae of neovascularization and inflammatory eye disease cause many grafts to undergo irreversible immunological rejection. Furthermore, in the case of corneal dystrophies, the original disease may recur in the graft. New therapeutic options for diseases of the cornea and ocular surface are now being actively explored in experimental animals and in clinical trials. Antibody-based biologics are being tested for their ability to reduce blood and lymphatic vessel ingrowth into the cornea, and to reduce inflammation. Many new biomaterials are being examined for their capacity to transfer drugs and corneal epithelial cell progenitor cells to the ocular surface and anterior segment of the eye. New component-cell corneal transplantation procedures that may reduce the risk of immunological rejection have been developed and are already in clinical practice. Finally, gene therapy is being tested in experimental animals to improve the outcomes of corneal transplantation, and to halt or reverse the pathophysiology of some corneal dystrophies. ... Read more

Tolerance Induction in Hemophilia A Animal Models: Battling Inhibitors with Antigen-specific Immunotherapies

Abstract: Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes). ... Read more

Novel Therapeutic Approaches for Leber's Hereditary Optic Neuropathy

Abstract: Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-to-treat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy. ... Read more

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