Gene therapy applications for fracture-healing

Biologic therapies to promote fracture-healing such as use of bone morphogenetic proteins (BMPs) are being increasingly employed in multiple clinical scenarios. However, it has been challenging to design therapies that deliver sufficient quantities of protein over a sustained time period. A potential solution is the application of gene therapy that transfers genetic information to host cells at the fracture site, resulting in the continuous and localized production of the desired proteins. This approach has demonstrated tremendous potential in preclinical animal models of fracture-healing. This article will review the current state of gene therapy approaches to fracture-healing with an emphasis on potential clinical applications.     

Gene therapy for spinal cord injury and disease

An incomplete understanding of the pathological processes involved in neurodegeneration and dysfunction of spinal cord injuries and diseases makes these disorders difficult to treat. Repair of damaged or genetically impaired spinal cord also has been limited by the complexity, cellular heterogeneity, and relative inaccessibility of the tissue. Thus, therapeutic options for the treatment of either chronic spinal cord diseases such as amyotrophic lateral sclerosis or acute spinal cord injuries have been rather limited. Potential new therapeutic targets are being identified as our understanding of the molecular pathology involved in neural injury and regeneration increases. Recent advances in gene transfer techniques have made gene therapy a more realistic and viable strategy for the treatment of a broad range of spinal cord disorders. This review summarizes the current state of knowledge regarding the limitations and recent advances in gene therapy and potential application of this technology toward spinal cord injury and disease.     

Gene therapy approach for disc degeneration and associated spinal disorders

Disc degeneration is deeply associated with many spinal disorders and thus has a significant clinical impact on society. The currently available surgical treatment often necessitates removing a pathological disc and spinal fusion. However, it is also well known that these surgical treatments have many potential problems including invasion and cost. Therefore, biological approaches for regenerating these pathological discs have received much attention. Gene therapy is one of these biological approaches. Gene therapy involves the transfer of genes to cells so the recipient cells express these genes and thereby synthesize the RNA and protein they encode in a continuous fashion. One of the significant advantages of gene therapy is that we can expect a lasting duration of biological effect which is potentially beneficial for most disc degeneration associated disorders, as they are, by nature, chronic conditions. Originally, gene therapy was mediated by viral vectors, but recent technological progress has enabled us to opt for non-virus-mediated gene therapy for the disc. Furthermore, the development of the RNA interference technique has enabled us to down-regulate a specific gene expression in the disc opening the door for a new generation of intradiscal gene therapy.

     

Gene therapy for osteoinduction.

One application of gene therapy that holds great promise is the stimulation of bone formation. Gene therapy offers several potential advantages over other methods of osteoinduction and current research suggests that it may be a feasible treatment option for the orthopedic surgeon in the near future. This article reviews the basic concepts and strategies of gene therapy and evaluates the current research using gene therapy to induce bone formation and enhance healing.     

Gene therapy for heart failure

Congestive heart failure (CHF) remains a leading cause of morbidity and mortality in the United States and in many other countries. Current heart failure therapies, including multidrug treatment regimens, biventricular pacing, and mechanical support such as left ventricular assist devices, are often hindered by limited benefits or significant associated procedural complications or side effects. Therefore, new forms of treatment, which could ideally target the underlying biological processes affecting the ailing cardiomyocyte, would be of significant potential benefit to the population of individuals with CHF. Gene transfer strategies, including modification of cellular contractile signaling and regulatory pathways, represent a promising new form of such biologic therapy for heart disease.     

Gene therapy for prostate cancer

In this section there are, as usual, four papers of general interest. The use of gene therapy has become topical, but is in need of further development. Its current status in prostate cancer is updated by the authors from London. In a mini‐review on what is termed ‘hypospadiology’, David Thomas reports on a topic that is one of the most commonly written about in paediatric urology. The authors from Israel review abdominal compartment syndrome, an important complication seen in critically ill patients. Finally, Jim Gillespie introduces us to his interesting views on the origin of the overactive bladder and sensory urgency.     

Gene therapy for esophageal cancer

Esophageal cancer is a highly malignant disease in which progression is observed in most patients even at the first medical examination. Neoadjuvant cytoreduction treatments are frequently used for the purpose of tumor down-staging, increasing the resection rate, and possibly improving survival. Although combination therapy with radiation and anticancer agents is available, no satisfactory treatment regimen has yet been established due to the development of resistance. Based on the concepts of genetic alteration in carcinogenesis, cancer gene therapy has been developing rapidly. We previously reported the growth inhibitory effect of adenovirus-mediated wild-type p53 gene transfer into esophageal squamous carcinoma cell lines. After extensive preclinical study of p53 gene therapy in vitro and in vivo, we are conducting a phase I/II clinical trial. The target of this trial is patients with unresectable esophageal cancer resistant to chemoradiotherapy. As of December 1, 2001, 8 candidates had been admitted to our hospital. After extensive examination, 4 patients were enrolled in this trial. After giving informed consent, the first patient received injections of Ad5 CMV-p53 on December 19, 2000. No serious adverse events have occurred so far in these patients, and the trial has been conducted safely.     

Gene therapy for heart failure

Pharmacological, device, and surgical therapies can be used in the management of heart failure. Because those conventional therapies are not effective in patients with the most severe heart failure, gene therapy is expected to become a viable alternative. The molecular pathways that contribute to the development of heart failure have been clarified in recent years. Specific molecular interventions have been evaluated in heart failure models, and the results indicate the potential for gene transfer strategies that are customized to target the individual molecular defects responsible for heart failure. Gene transfer studies have shown that modulating calcium homeostasis, manipulating beta-adrenergic receptor signaling, and augmenting cardiomyocyte resistance to apoptosis can be expected to be useful therapeutic modalities.     

Gene therapy for bladder cancer

Tumor-suppressor genes can be transferred into tumor cells in vivo using a replication-defective adenoviral vector. P53 mutations are frequent in bladder cancer, and adenovirus-mediated p53 gene transfer is growth-inhibitory to bladder cancer cells in vitro. The vector Ad5CMV-P53, which contains human wild-type p53, is being administered intravesically to patients with bladder cancer in a phase I clinical trial. The results of this study will provide the basis for phase II and phase III trials in which gene therapy will be integrated with existing therapies for improved local control and opportunities for bladder preservation.     

Gene therapy for urologic cancer

Advances in molecular technology and the completion of the human genome project have ushered in a new era of medicine, that of gene therapy. In every field of medicine, investigators are developing gene therapeutics in an attempt to cure diseases. Urologic oncology is no exception. Herein, we review the current status of gene therapy for urologic malignancy. Included is an overview of advances in gene delivery systems and immunology, which are driving forces for gene therapy research. Finally, we review the current gene therapy trials and experimental approaches for urologic malignancy.