UNITED THERAPEUTICS IS AMONG THE COMPANIES IN THE BIOTECHNOLOGY INDUSTRY WITH THE HIGHEST EPS GROWTH (UTHR, GENZ, ALXN, CELG, CEPH)

Mar 30, 2011 (SmarTrend(R) News Watch via COMTEX) -- Below are the top 5 companies in the Biotechnology industry ranked by the year-over-year expected EPS growth rate. The long-term growth rate is the expected annual increase in operating EPS over the next three to five years.
United Therapeutics (NASDAQ:UTHR) EPS is expected to grow 283.1% year-over-year, better than the company's long-term growth rate of 60%. Based on the forward P/E of 12.7x its PEG ratio is 0.21, which signifies a discount in value relative to growth.
Genzyme (NASDAQ:GENZ) EPS is expected to grow 234.8% year-over-year, better than the company's long-term growth rate of 19.3%. Based on the forward P/E of 18.6x its PEG ratio is 0.96, which signifies a discount in value relative to growth.
Alexion Pharmaceuticals (NASDAQ:ALXN) EPS is expected to grow 118.3% year-over-year, better than the company's long-term growth rate of 38.8%. Based on the forward P/E of 43.9x its PEG ratio is 1.13, which signifies a premium valuation given for growth.
Celgene (NASDAQ:CELG) EPS is expected to grow 60% year-over-year, better than the company's long-term growth rate of 25.7%. Based on the forward P/E of 16.4x its PEG ratio is 0.64, which signifies a discount in value relative to growth.
Cephalon (NASDAQ:CEPH) EPS is expected to grow 49.3% year-over-year, better than the company's long-term growth rate of 10.2%. Based on the forward P/E of 7x its PEG ratio is 0.68, which signifies a discount in value relative to growth.
SmarTrend currently has shares of Genzyme in an Uptrend and issued the Uptrend alert on July 23, 2010 at $60.20. The stock has risen 26.3% since the Uptrend alert was issued.

Angiopoiesis and bone regeneration via co-expression of the hVEGF and hBMP genes from an adeno-associated viral vector in vitro and in vivo

Angiopoiesis and bone regeneration via co-expression of the hVEGF and hBMP genes from an adeno-associated viral vector in vitro and in vivo

Chen Zhang¹, Kun-zheng Wang¹, Hui Qiang¹, Yi-lun Tang¹, Qian Li², Miao Li² and Xiao-qian Dang¹

1. ¹Department of Orthopedic Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
2. ²Department of Ultrasound, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China

Correspondence: Xiao-qian Dang, E-mail dang_xiaoqian@sohu.com

Received 22 February 2010; Accepted 6 May 2010; Published online 28 June 2010.

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Abstract

Aim:

 

To investigate the therapeutic potential of adeno-associated virus (AAV)-mediated expression of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP).

Methods:

 

Four experimental groups were administered the following AAV vector constructs: rAAV-hVEGF₁₆₅-internal ribosome entry site (IRES)-hBMP-7 (AAV-VEGF/BMP), rAAV-hVEGF₁₆₅-GFP (AAV-VEGF), rAAV-hBMP-7-GFP (AAV-BMP), and rAAV-IRES-GFP (AAV-GFP). VEGF₁₆₅ and BMP-7 gene expression was detected using RT-PCR. The VEGF₁₆₅ and BMP-7 protein expression was determined by Western blotting and ELISA. The rabbit ischemic hind limb model was adopted and rAAV was administered intramuscularly into the ischemic limb.

Results:

 

Rabbit bone marrow-derived mesenchymal stem cells (BMSCs) were cultured and infected with the four viral vectors. The expression of GFP increased from the 7th day of infection and could be detected on the 28th day post-infection. In the AAV-VEGF/BMP group, the levels of VEGF165 and BMP-7 increased with prolonged infection time. The VEGF₁₆₅ and BMP-7 secreted from BMSCs in the AAV-VEGF/BMP group enhanced HUVEC tube formation and resulted in a stronger osteogenic ability, respectively. In rabbit ischemic hind limb model, GFP expression increased from the 4th week and could be detected at 8 weeks post-injection. The rAAV vector had superior gene expressing activity. Eight weeks after gene transfer, the mean blood flow was significantly higher in the AAV-VEGF/BMP group. Orthotopic ossification was radiographically evident, and capillary growth and calcium deposits were obvious in this group.

Conclusion:

 

AAV-mediated VEGF and BMP gene transfer stimulates angiogenesis and bone regeneration and may be a new therapeutic technique for the treatment of avascular necrosis of the femoral head (ANFH).

Keywords:

adeno-associated virus; vascular endothelial growth factor; bone morphogenetic protein (BMP); avascular necrosis of the femoral head (ANFH); gene therapy

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Introduction

Recent insight into the pathogenesis of avascular necrosis of the femoral head (ANFH) has not identified satisfactory methods to increase blood circulation in necrotic areas of the femoral head, to promote bone regeneration, or to prevent osteonecrosis. The rapid development of gene therapy technology is increasingly recognized as a new therapeutic option for the treatment of ANFH, especially through therapeutic neovascularization and bone formation. Among growth factors, vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP) play important roles and have been extensively studied.

The VEGF family of growth factors is one of the most important cytokine families involved in angiogenesis. These factors promote the division of vascular endothelial cells and induce angiopoiesis. VEGF growth factors are essential for bone formation and repair during the bone regeneration process, which directly attracts endothelial cells and osteoclasts and enhances the differentiation of osteoblasts^{1, 2}. BMP growth factors are the only signaling molecules that are individually sufficient for the induction of bone formation at orthotopic and heterotopic sites. They have defined roles in stimulating the proliferation and differentiation of mesenchymal and osteoprogenitor cells and have efficient bone induction activity^{3, 4}. Because bone formation is a coordinated process involving the BMP and VEGF growth factors^{5, 6}, orchestrating the timing with which these two factors are expressed may greatly enhance this process.

Choosing a safe and effective vector system to transfer and correctly express a target gene during gene therapy is important. Several different strategies have been examined for the delivery of genes of interest, including the use of naked DNA or an adenoviral vector. Treatment with naked DNA is simple and well tolerated by the recipient organism due to its low toxicity and weak induction of immune responses. However, the transduction efficiency is significantly lower when compared with other methods. The adenovirus has frequently been the vector of choice for gene transfer because it is able to transduce a variety of cells with high efficiency. However, adenoviral vectors have major limitations, including a lack of sustained expression, the antigenicity of viral proteins that are targeted by both humoral immunity and cytotoxic T lymphocytes, and possible toxicity at high doses. However, there are many inherent features of the adeno-associated virus system that make it an attractive option as a human viral vector. AAV is a non-pathogenic, defective human parvovirus that requires the presence of a helper virus, such as adenovirus or herpes virus, for productive infection^{7, 8}. Other advantages of this vector system include its low immunogenicity, its ability to transduce both dividing and non-dividing cells, the potential to integrate into specific sites, its ability to achieve long-term gene expression (even in vivo), and its broad tropism, allowing for the efficient transduction of diverse organs⁹. These features make AAV attractive and efficient for gene transfer in vitro and local injection in vivo.

To enhance neovascularization and bone regeneration during osteonecrosis therapy, we constructed adeno-associated viruses co-expressing hVEGF₁₆₅ and hBMP-7 (rAAV-VEGF₁₆₅-IRES-BMP-7) and detected their effect on gene expression and biological activity in vitro and in vivo. These data demonstrate the synergistic action of these two genes and may provide a new therapeutic option for ANFH.

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Materials and methods

Materials and reagents

The rAAV-hVEGF₁₆₅-IRES-hBMP-7 (AAV-VEGF/BMP), rAAV-hVEGF₁₆₅-GFP (AAV-VEGF), rAAV-hBMP-7-GFP (AAV-BMP), and rAAV-IRES-GFP (AAV-GFP) plasmids were constructed by Dr Xiang-hui HUANG. Human embryonic kidney cells-293 (HEK-293) and human umbilical vein endothelial cells (HUVECs) were obtained from the Department of Orthopedic Surgery in the Second Affiliated Hospital of Xi'an Jiaotong University. Male New Zealand rabbits (two months old, weighing 2.0–3.0 kg) were obtained from the experimental animal center of Xi'an Jiao Tong University. All animal protocols followed the recommendations and guidelines of the National Institutes of Health and were approved by the Xi'an Jiao Tong University Animal Care and Use Committee. The AAV helper-free system was obtained from Stratagene (La Jolla, CA, USA). A schematic representation of the structure of the plasmids in the AAV Helper Free System is provided in Figure 1A

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