Vasoactive Intestinal Peptide Derivatives
Overview
Vasoactive intestinal peptide (VIP) and derivative VIP appear to be promising new ways to treat pulmonary arterial hypertension. A study conducted at the University of Vienna involved eight patients with pulmonary arterial hypertension. Inhalation of VIP increased 6MWD from 296 m ± 138 m at baseline to 409 m ± 102 m in three months, reduced mean pulmonary artery pressure, increased cardiac output, and increased mixed venous oxygen saturation. The following paragraphs discuss Mondobiotech’s VIP derivative aviptadil.
Mechanism Of Action
VIP inhibits platelet activation and smooth-muscle-cell proliferation and dilates pulmonary vascular smooth muscle through activation of adenylate cyclase.
Aviptadil
Mondobiotech is developing an inhaled formulation of aviptadil for pulmonary arterial hypertension. The company recently signed an agreement with Bachem, which will produce and supply the agent. The European Medicines Agency has granted aviptadil orphan drug status for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Company literature states the product is based on VIP and belongs to the glucagon-secretin super-family. Aviptadil consists of 28 amino acids and is synthetically produced. Its mechanism, although not fully defined, follows the general mechanism of action outlined for VIPs. Phase II trials for pulmonary arterial hypertension are under way in Europe.
Overview
For many years, researchers have envisioned using gene-based medicines — which introduce a new gene or block the expression of a gene — to cure or slow the progression of disease. A major advance in gene-based medicine occurred in June 2000 when a working draft of the human genome was announced to the scientific community. Researchers in the field of genomics have continued to make rapid progress identifying genes involved in human diseases and determining their function. Although this progress has generated much hope for gene-based medicines, several hurdles remain, including the limited efficacy of gene transfer, immune responses to vectors, and problems with vector specificity. Two gene therapy programs are under way for pulmonary arterial hypertension: a collaboration between Aradigm and GeneRx + , which is discussed in further detail in the following section; and a discovery program at Northern Therapeutics directed by Duncan Stewart of the University of Toronto. Northern Therapeutics initiated the Pulmonary Hypertension: Assessment of Cell Therapy (PHACeT) single-center trial in January 2005. This 18-patient study will establish the safety and tolerability of the therapeutic injection of endothelial precursor cells to regenerate the small pulmonary arteries of the lung. The precursor cells, which are initially collected from the patient’s bloodstream prior to undergoing genetic modification, are delivered to the pulmonary artery via a catheter.
Mechanism Of Action
Gene therapy involves the replacement, removal, or introduction of genes or other manipulation of genetic material. Gene therapies contain large DNA molecules that make up an entire gene and may include part of a vector or other delivery vehicle.
Coxagen
U.S.-based companies Aradigm and GeneRx + are collaborating on the development of the pulmonary delivery of one of GeneRx + ‘s lead gene drug candidates, coxagen, to treat pulmonary hypertension. Aradigm specializes in pulmonary drug delivery, while GeneRx + is involved in protein and gene-based technologies. Coxagen is a cyclooxygenase gene encoded in a plasmid vector formulated with a cationic lipid. This particular gene therapy involves delivering the gene to the lungs via aerosol administration. It is at the preclinical stage.
GeneRx + reports that in both large and small animal studies, coxagen has been shown to increase specifically endogenous generation of protective prostanoids in the lungs, to prevent pulmonary hypertension produced by administration of endotoxin, and to reduce pulmonary vascular reactivity. Investigations of lung structure and function demonstrate no adverse effects of aerosol administration. The company also states the product’s therapeutic effects last for approximately a week following a single administration. GeneRx + is hoping this product will qualify for orphan drug status from the FDA.
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