Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease

• Published in: Gene therapy Vol. 19; no. 3; pp. 264 - 270
• Main Authors: Niebuhr, A, Henry, T, Goldman, J, Baumgartner, I, van Belle, E, Gerss, J, Hirsch, A T, Nikol, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2012; Nature Publishing Group
• Subjects: Aged; Aged, 80 and over; Amputation; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiogenesis; Applied cell therapy and gene therapy; Arteries; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer; Cardiovascular diseases; Care and treatment; Cell Biology; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cerebral infarction; Clinical trials; Data processing; Development and progression; Fatigue; Female; Fibroblast growth factor 1; Fibroblast Growth Factor 1 - genetics; Fibroblast Growth Factor 1 - metabolism; Fibroblast growth factors; Fibroblasts; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - adverse effects; Growth factors; Health. Pharmaceutical industry; Human Genetics; Humans; Industrial applications and implications. Economical aspects; Injections, Intramuscular; Intermittent claudication; Ischemia; Leg; Limbs; Male; Medical sciences; Middle Aged; Molecular and cellular biology; Muscles; Myocardial infarction; Myocardial Infarction - complications; Nanotechnology; Neoplasms - complications; original-article; Pain; Patient safety; Patients; Peripheral Arterial Disease - complications; Peripheral Arterial Disease - genetics; Peripheral Arterial Disease - mortality; Peripheral Arterial Disease - therapy; Peripheral vascular diseases; Physiological aspects; Placebos; Renal function; Retinopathy; Risk factors; Safety; Stroke; Stroke - complications; Survival Analysis; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Vascular diseases; Vein & artery diseases; Germany; registry; peripheral artery disease; long-term follow-up; angiogenesis; safety; Angiogenesis; NV1FGF; Blood vessel; Non viral vector; Circulatory system; Gene therapy; Artery; Genetic transfer
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.85

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 ( NV1FGF ), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.