The Digest/The Wire

OPEN IN VIEWER

PTH—It Does a Body Good

page: 1344

Hypoparathyroidism is an endocrine disorder in which the parathyroid glands in the neck do not produce enough parathyroid hormone (PTH). Hypoparathyroidism can result in hypocalcemia, which is a serious medical condition. According to Dr. Gianlorenzo Dionigi, director of the Endocrine Surgery Research Center at the University of Insubria in Varese, Italy, “hypocalcemia presentations vary widely, from asymptomatic to life-threatening situations. In severe cases, hypocalcemia may lead to arrhythmias, hypotension, and heart failure. Some patients may manifest digitalis insensitivity. In addition to acute seizures or tetany, hypocalcemia may lead to basal ganglia calcification, parkinsonism, hemiballisms, and choreoathetosis.” Long-term PTH treatment is difficult as PTH has a short half-life and must be injected daily. In this issue, Chou and colleagues at the Chang Gung University College of Medicine in Kaohsiung Hsien, Taiwan, demonstrate the feasibility of PTH gene therapy. The authors orally deliver nonionic polymeric micelles containing a CMV promoter-driven PTH plasmid to rats after parathyroidectomy. This treatment led to elevated levels of calcium that were maintained for up to 4 weeks. Importantly, whereas one third of the rats in the control group died of hypocalcemia, none of the CMV-PTH-treated rats died. The advantage of this approach is that it achieves a more prolonged release of PTH and the gene is delivered orally. Clinical translation will be challenging, with the next steps including proof-of-concept in larger animals. (sk)

Genetic Adjuvant Vaccines Shocked

page: 1269 and 1291

OPEN IN VIEWER

Certain antigens have proven refractory to classic vaccine strategies and have fueled research and discovery efforts on the part of both academia and industry to develop improved vaccine platforms and technologies. HIV and cancer, in particular, have moved the conventional vaccine field toward genetic and cell-based vaccines. One of the most elegant strategies for developing genetic vaccines stemmed from the groundbreaking paper by Wolff et al., ¹ which showed that direct injection of DNA into muscle resulted in transduction. The impact of this observation on the future development of vaccines did not escape the authors. In the final paragraph of this paper they state that “the intracellular expression of genes encoding antigens may provide alternative approaches to vaccine development.” Dr. Jeffrey B. Ulmer, who is the Global Head of External Research at Novartis Vaccines and Diagnostics in Cambridge, Massachusetts, adds that indeed “one of the most promising approaches to this end has been plasmid DNA vaccines, due to their simplicity and wide utility in animal models. However, DNA vaccines have so far lacked potency in humans and an enabling technology is needed.”

To render DNA vaccines more immunogenic, several strategies have been tried. One way to boost the immunogenicity of inherently weaker or difficult antigens is to provide coexpression of a protein with properties that may enhance the immunogenicity and, in fact, serve as a genetically encoded adjuvant. In this issue of Human Gene Therapy, two groups report on advanced studies using genetic adjuvants in nonhuman primates ( Martinon et al. , p. 1291) and humans ( Low et al. , p. 1269).

A second focus of technological advance has been on the method of delivering a DNA vaccine to skin or muscle. Dr. Ulmer states that, as Martinon et al. demonstrate, “electroporation (EP) in situ is very effective at facilitating DNA vaccine delivery, even in large animals such as nonhuman primates. Currently, there are several ongoing early-stage human clinical trials to evaluate the safety and effectiveness of EP. Low et al. demonstrate for the first time that, like in animal models, EP enhances DNA vaccine potency and appears to be safe and well tolerated in humans. These data support further clinical evaluation of EP as a means to overcome the human species barrier for DNA vaccines.” (lv)

A Niche for Stem Cells in the Lung?

page: 1329

OPEN IN VIEWER

The clinical use of stem cells faces many obstacles. In a paper by Leblond et al. , several of these hurdles were encountered when developing a protocol for stem cell therapies in the lung. Not only does one need to identify and isolate the appropriate stem cell for the right application, genetic modification may be required to generate the appropriate cell, which is associated with its own risks. Ultimately, cells must be deposited in the appropriate locale and integrated into the target tissue in an ordered fashion. The potential, however, is significant and the technology may eventually provide new treatment options for respiratory disease.

Dr. Vladimir Serikov from the Children's Hospital of Oakland, Oakland, California and Professor Michael A. Matthay of the Department of Medicine and the Cardiovascular Research Institute at the University of California in San Francisco, California comment that the “study by Leblond and co-workers investigated survival and engraftment of different types of stem cells to the injured lung, using a novel method of stem cell delivery via the airways. This careful study used several robust approaches for labeling and tracing cells with different types of reporter genes and the study was performed systematically, with a large number of observations, several different methods of tracer detection, and multiple controls. The authors report that there was a limited and short-term presence of transplanted stem cells which survived in injured airways for less than 7 days. Noninjured lung served as a robust barrier to transplanted cells. As the authors themselves point out, they did not have phenotypic information on the surviving cells. Thus, this study demonstrates that cell-based and gene-based therapies for the lung encounter the innate mechanisms of lung defense. These issues must be accounted for while planning future experimental and clinical trials.” (lv)

Science wire

New Blood Vessels: Courtesy of Gene Therapy and Stem Cells

OPEN IN VIEWER

Angiogenesis is an essential process during development; growth of a vascular system is one of the earliest events in organogenesis. This process also occurs in adulthood, and is critical for wound healing and restoration of blood flow to injured tissues. Inadequate blood vessel growth leads to poor circulation and tissue death and underlies disease conditions such as coronary heart disease, stroke, and delayed wound healing. As such, controlled angiogenesis is considered an important component of tissue regeneration and the treatment of ischemic diseases. Yang et al., in the laboratory of Daniel G. Anderson at the Massachusetts Institute of Technology now show that a combined stem cell/gene therapy approach can be used to induce therapeutic angiogenesis in mice. ¹ The authors used biodegradable nanoparticles to transfect human mesenchymal stem cells (hMSCs) and human embryonic stem cell-derived cells (hESdCs) with the angiogenic vascular endothelial growth factor (VEGF) gene. Transplantation of the VEGF-expressing cells was found to induce significantly more angiogenesis, skeletal muscle protection, and limb salvage than nonmodified cells in mice with hind limb ischemia. Examination of ischemic limbs 4 weeks after cell transplantation revealed reduced tissue degeneration and minimal fibrosis in the mice treated with VEGF-transfected stem cells compared with animals treated with nonmodified cells. Dr. Alberto Crottogini, Chairman of the Department of Physiology at Favaloro University in Buenos Aires, Argentina, states that “the study by Yang et al. is an important contribution in this field [angiogenesis].” He notes that “VEGF has been previously shown to induce, in addition to angiogenesis and arteriolar neoformation, a cardiomyogenic effect which limits infarct size in large mammals with acute or progressive coronary occlusion. Yang's approach should therefore be tested in animal models of myocardial diseases characterized by contractile cell loss.” (sk)

Industry wire

OPEN IN VIEWER

Celladon Corporation announced that its SERCA2a programs for the treatment of acute and chronic heart failure were evaluated by Windhover and an independent expert panel and found to be one of the 10 most interesting cardiovascular projects available for partnering. Windhover Information provides analysis and commentary on health care business strategy, industry deal making, marketplace trends, and the world of medical start-ups. This endorsement for Celladon's programs has also been paralleled by financial support; the company has raised more than $20 million U.S. dollars in a recent venture round. These moneys will guarantee company operations until the current AAV-based clinical trial for people with congestive heart failure is concluded.

Inovio Biomedical, a San Diego, California-based DNA vaccine company, presented data on what it calls a first step toward a universal vaccine against influenza. A combination of synthetic consensus H1N1 influenza vaccine candidates yielded protective antibody responses against the novel pandemic influenza A/H1N1 (2009) in 100% of tested ferrets. The company touts its SynCon process as being able to generate optimal consensus sequences between multiple flu subtypes to provide wide cross-reactivity of the derived vaccine. Inovio has initiated cGMP clinical manufacturing of the H1N1 SynCon vaccine candidate and remains focused on the development of a universal vaccine for both seasonal and pandemic influenza strains.

Ark Therapeutics received positive feedback from the U.K. Governmental Medicines and Healthcare Products Regulatory Agency regarding EG013 for severe fetal growth restriction. The VEGF-based gene therapy, which uses an adenoviral vector, is ready for evaluation in a phase I clinical trial. Severe fetal growth restriction can be a terminal condition in which, because of insufficient blood supply to the placenta, growth is significantly retarded and long-term neurological problems in surviving infants or premature death may occur. At present, there is no effective treatment. (lv)

Regulatory wire

Stimulating Research with ARRA

OPEN IN VIEWER

The American Recovery and Reinvestment Act of 2009 (ARRA) was enacted by the U.S. Congress and President Barack Obama in February 2009. This two-year plan is intended to provide a stimulus to the U.S. economy in the wake of the international economic downturn; its measures, nominally worth $787 billion, include a bevy of federal tax cuts, and domestic spending in education, health care, infrastructure, the energy sector, and scientific research. With respect to scientific research, $8.9 billion was allocated to organizations such as the National Science Foundation and NASA, while $10.4 billion was committed to health and biomedical research and construction of National Institutes of Health (NIH) facilities, of which $9 billion is earmarked for extramural funding. In a September 20, 2009 speech at the NIH main campus, President Obama noted that these funds collectively constitute “the single largest boost to biomedical research in history. ¹ ”

Extramural funding is being distributed by the NIH across four broad categories, including the following: (1) peer-reviewed, highly meritorious research grant applications (e.g., R01s and others) that can be accomplished in 2 years or less; (2) new research applications; (3) targeted supplements to current grants; and (4) new types of activities such as the NIH Challenge Grant and Grand Opportunities (GO) programs. The Challenge Grant program was designed to address specific scientific and health research challenges in biomedical and behavioral research that can potentially benefit from significant 2-year jumpstart funds. Challenge Area grants are intended to focus on specific knowledge gaps, scientific opportunities, new technologies, data generation, or research methods that would benefit from an influx of funds to quickly advance the area in significant ways. The Challenge initiative generated more than 20,000 proposals of which about 4% were funded. GO grant support to large, high impact applications that have a high likelihood of enabling growth and investment in biomedical research and development. 376 of these grants were awarded nationwide. ²

An in-depth search of the NIH RePORTER database conducted by Human Gene Therapy has revealed that of the $5 billion spent by the NIH on extramural research funding during the 2009 fiscal year, $229.4 and $72.1 million have gone to stem cell and gene therapy-related research, respectively; this constitutes 4.5 and 1.4% of total ARRA funding for 2009. These percentages are in line with the NIH's total research spending for gene therapy and stem cell research in fiscal year 2008. By comparison, the NIH spent nearly $100 million for autism, $750 million for heart disease research, and $175 million for The Cancer Genome Atlas in 2009. ¹ (sk & lv)