Gene therapy – when a simple concept meets a complex reality

In theory, gene therapy is a simple concept which holds great promise as a cure for disease. In practice, however, considerable obstacles have to be overcome, including problems with safe and efficient gene delivery and stable gene expression. This review gives an overview on the history of gene therapy and analyses some of the problems that have so far prevented the establishment of a successful clinical protocol. The future prospects of gene therapy are discussed.     

When cell cycle meets development

The recent Company of Biologists workshop 'Growth, Division and Differentiation: Understanding Developmental Control', which was held in September 2011 at Wiston House, West Sussex, UK, brought together researchers aiming to understand cell proliferation and differentiation in various metazoans, ranging from flies to mice. Here, we review the common themes that emerged from the meeting, highlighting novel insights into the interplay between regulators of cell proliferation and differentiation during development.     

Post-genomic vaccine development

For over a century, vaccines were developed according to Pasteur's principles of isolating, inactivating and injecting the causative agent of an infectious disease. The availability of a complete microbial genome sequence in 1995 marked the beginning of a genomic era that has allowed scientists to change the paradigm and approach vaccine development starting from genomic information, a process named reverse vaccinology. This can be considered as one of the most powerful examples of how genomic information can be used to develop therapeutic interventions, which were difficult or impossible to tackle with conventional approaches. As the genomic era progressed, it became apparent that multi-strain genome analysis is fundamental to the design of universal vaccines. In the post-genomic era, the next challenge of the vaccine biologist will be the merging of the vaccinology with structural biology.     

Optimizing vaccine development

Optimizing the development of modern molecular vaccines requires a complex series of interdisciplinary efforts involving basic scientists, immunologists, molecular biologists, clinical vaccinologists, bioinformaticians and epidemiologists. This review summarizes some of the major issues that must be carefully considered. The intent of the authors is to briefly describe key components of the development process to give the reader an overview of the challenges faced from vaccine concept to vaccine delivery. Every vaccine requires unique features based on the biology of the pathogen, the nature of the disease and the target population for vaccination. This review presents general concepts relevant for the design and development of ideal vaccines protective against diverse pathogens.     

Plant development meets cell proliferation in Madrid.

Cell division is intimately intertwined with plant development, and the mechanisms that link the control of cell proliferation and differentiation with the processes of organogenesis, morphogenesis, and growth are starting to be understood. A recent Juan March meeting explored this interface, and revealed a rich seam of exciting work that is leading toward an integrated view of the role of cell proliferation in the unfolding of developmental programs.     

Gene therapy

Summary A number of techniques are available for insertion of new genetic information into mammalian cells. Some of these have been used successfully for genetic modification of germ line cells and somatic cells of living animals. Some of these techniques may be applicable to treatment of some of the genetic diseases of man, once problems related to the control of expression of introduced genes are solved.     

Gene correction in patient-specific iPSCs for therapy development and disease modeling

The discovery that mature cells can be reprogrammed to become pluripotent and the development of engineered endonucleases for enhancing genome editing are two of the most exciting and impactful technology advances in modern medicine and science. Human pluripotent stem cells have the potential to establish new model systems for studying human developmental biology and disease mechanisms. Gene correction in patient-specific iPSCs can also provide a novel source for autologous cell therapy. Although historically challenging, precise genome editing in human iPSCs is becoming more feasible with the development of new genome-editing tools, including ZFNs, TALENs, and CRISPR. iPSCs derived from patients of a variety of diseases have been edited to correct disease-associated mutations and to generate isogenic cell lines. After directed differentiation, many of the corrected iPSCs showed restored functionality and demonstrated their potential in cell replacement therapy. Genome-wide analyses of gene-corrected iPSCs have collectively demonstrated a high fidelity of the engineered endonucleases. Remaining challenges in clinical translation of these technologies include maintaining genome integrity of the iPSC clones and the differentiated cells. Given the rapid advances in genome-editing technologies, gene correction is no longer the bottleneck in developing iPSC-based gene and cell therapies; generating functional and transplantable cell types from iPSCs remains the biggest challenge needing to be addressed by the research field.     

Angiogenesis meets immunology: cytokine gene therapy of cancer

Delivery of cytokine genes at the tumor site in pre-clinical models has been shown to recruit host inflammatory cells followed by inhibition of tumor growth. This local effect is often accompanied by systemic protection mediated by the immune system, mainly by CD8(+) T and NK cells. On this basis, cytokine gene-transduced tumor cells have widely been used as vaccines in clinical trials, which have shown good safety profiles and some local responses but substantial lack of systemic efficacy. Are these findings the end of the story? Possibly not, if major improvements will be attained in the coming years. These should be directed at the level of gene selection and delivery, in order to identify the optimal cytokine and achieve efficient and durable cytokine expression, and at the level of improving immune stimulation, i.e. by co-administration of co-stimulatory molecules including B7 and CD40, or boosting the expression of tumor antigens or MHC class I molecules. Interestingly, some of the cytokines which have shown encouraging anti-tumor activity, including IFNs, IL-4, IL-12 and TNF-alpha, are endowed with anti-angiogenic or vasculotoxic effects, which may significantly contribute to local tumor control. Therapeutic exploitation of this property may result in the design of novel approaches which, by maximizing immune-stimulating and anti-angiogenic effects, could possibly lead to starvation of established tumors in patients.