From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB).

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds with significant morbidity, impaired quality of life, and early mortality. RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1, the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in COL7A1 have been reported to cause dystrophic epidermolysis bullosa (DEB), which may be inherited in an autosomal dominant (DDEB) or autosomal recessive pattern (RDEB), the incidence and prevalence of RDEB is not well defined. To date, the widely estimated incidence (0.2-6.65 per million births) and prevalence (3.5-20.4 per million people) of RDEB has been primarily characterized by limited analyses of clinical databases or registries. METHODS: Using a genetic modelling approach, we use whole exome and genome sequencing data to estimate the allele frequency of pathogenic variants. Through the ClinVar and NCBI database of human genome variants and phenotypes, DEB Register, and analyzing premature COL7A1 termination variants we built a model to predict the pathogenicity of previously unclassified variants. We applied the model to publicly available sequences from the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) and identified variants which were classified as pathogenic for RDEB from which we estimate disease incidence and prevalence. RESULTS: Genetic modelling applied to the whole exome and genome sequencing data resulted in the identification of predicted RDEB pathogenic alleles, from which our estimate of the incidence of RDEB is 95 per million live births, 30 times the 3.05 per million live birth incidence estimated by the National Epidermolysis Bullosa Registry (NEBR). Using a simulation approach, we estimate a mean of approximately 3,850 patients in the US who may benefit from COL7A1-mediated treatments in the US. CONCLUSION: We conclude that genetic allele frequency estimation may enhance the underdiagnosis of rare genetic diseases generally, and RDEB specifically, which may improve incidence and prevalence estimates of patients who may benefit from treatment.

A novel series of conferences tackling the hurdles confronting the translation of novel cancer immunotherapies.

While there has been significant progress in advancing novel immune therapies to the bedside, much more needs to be done to fully tap into the potential of the immune system. It has become increasingly clear that besides practical and operational challenges, the heterogeneity of cancer and the limited efficacy profile of current immunotherapy platforms are the two main hurdles. Nevertheless, the promising clinical data of several approaches point to a roadmap that carries the promise to significantly advance cancer immunotherapy. A new annual series sponsored by Arrowhead Publishers and Conferences aims at bringing together scientific and business leadership from academia and industry, to identify, share and discuss most current priorities in research and translation of novel immune interventions. This Editorial provides highlights of the first event held earlier this year and outlines the focus of the second meeting to be held in 2013 that will be dedicated to stem cells and immunotherapy.

Financing development stage biotechnology companies: RMs vs. IPOs.

We examine reverse mergers (RMs) in the biotechnology industry and find that, when compared to initial public offerings (IPOs), RMs are smaller, have significantly lower market valuations relative to size, and generally invest less. We also find that RMs exhibit positive abnormal returns on the announcement date and throughout the first year after the RM event. In looking at liquidity measures, we find that RMs tend to be less liquid than IPOs and that illiquidity is greater during the six-month lock-up period following the RM event. Thus, RMs may be an appropriate alternative financing vehicle in capital intensive, high-risk biotechnology companies which require accessing deeper and larger pools of investors in public capital markets across multiple milestone periods in a "pay for progress" environment.

The effectiveness of risk management: an analysis of project risk planning across industries and countries.

This article examines the effectiveness of current risk management practices to reduce project risk using a multinational, multi-industry study across different scenarios and cultures. A survey was administered to 701 project managers, and their supervisors, in seven industries and three diverse countries (New Zealand, Israel, and Japan), in multiple languages during the 2002-2007 period. Results of this study show that project context--industry and country where a project is executed--significantly impacts perceived levels of project risk, and the intensity of risk management processes. Our findings also suggest that risk management moderates the relationship between risk level and project success. Specifically, we found that even moderate levels of risk management planning are sufficient to reduce the negative effect risk levels have on project success.

Ethics and the AIDS pandemic in the developing world.

Traditional ethics provide insight, but often fall short of guiding the complex biomedical ethical concerns of research conducted in developing countries. The need to create research within a framework that is appropriate to the social, medical, and political context of developing countries is examined through the current AIDS pandemic in sub-Saharan Africa. A specific case study focuses on this issue. Over 70 percent of the 40 million people with HIV/AIDS live in sub-Saharan Africa. With at least one in five African adults infected with the disease, sub-Saharan Africa is now acknowledged as the epicenter of HIV/AIDS. The scale and scope of the disease in the environment of a developing economy presents unique issues that challenge the role and practices of traditional ethics in healthcare research programs. Medical research within developing countries, particularly for HIV/AIDS, requires a distinctive approach. For these populations, investigators must incorporate new thinking into traditional biomedical research ethics which will address the role of innovation; access to treatment; the impact of fear, stigma, and denial; concerns around autonomy for vulnerable populations; capacity building; and sustainable care to communities. Since May 1999, Secure the Future, a philanthropic program that focuses on care and support for women and children infected and affected by HIV/AIDS, has attempted to fulfill these ethical concepts in its processes. The program is a public and private sector partnership between governments, communities, practitioners, academia, and Bristol-Myers Squibb Company to respond to AIDS in five countries in sub-Saharan African countries: Botswana, Lesotho, Namibia, South Africa, and Swaziland. To ensure symmetry between ethical principles and local context, collaborative projects undergo a comprehensive review process. This includes review and approval by a national secretariat to ensure projects support objectives of national policies and local communities; approval by an ethics committee comprised of participating institutions; blinded peer review; and an examination by an external advisory board comprised of local and international medical experts, persons living with AIDS (PLWA), religious communities, governments, and nongovernmental organizations (NGOs). An independent monitor also oversees the approved programs. Cost-effective and practical interventions against HIV/AIDS must encompass ethical approaches appropriate to the contexts of the respective developing countries. Lessons learned to date are to focus on innovation; establish unassailable ethical standards that are sensitive to local contexts; ensure transparent communications among partners and the broader community; and build sustainable capacity.