Münster, Germany -
Understanding and manipulating the formation of new blood vessels, a process called angiogenesis, has been one of the highly sought-after goals of the biotechnology industry. One the one hand, inhibition of angiogenesis is desirable in cancer, since tumors need new blood vessels to stay alive. On the other hand, angiogenesis stimulation could be a beneficial treatment for diseases such as ischemic heart failure and other types of conditions associated with poor circulation.
Critical limb ischemia is an advanced form of peripheral arterial disease that is associated with a high degree of morbidity and mortality. Due to the severe inhibition of circulation, patients with this condition experience pain in the affected limbs, even when resting, as well as an increased frequency of ulcers, many times which do not heal. The goal of current medical treatment of critical limb ischemia is to ameliorate pain, accelerate healing of ulcers, and increase the overall quality of life. Unfortunately at present there is no medical therapy that effectively addresses the causes of critical limb ischemia. Surgical (bypass) and percutaneous (stent placement) interventions are effective in some patients, however long term prognosis is dismal due to morbidy associated with surgery, and restenosis of inserted stents. Furthermore, patients with diffuse disease are not candidates for either treatments.
One method of stimulating angiogenesis is through administration of stem cell populations. For example, US Patent #6878371, assigned to Boston Scientific Scimed, covers intra alia "A method of forming new blood vessels in cardiac muscle tissue in a subject, wherein the subject is a human, which comprises: a) isolating autologous bone marrow-mononuclear cells from the human, wherein the autologous bone marrow-mononuclear cells are isolated from bone marrow; and b) transplanting locally into the cardiac muscle tissue an effective amount of the autologous bone-marrow mononuclear cells, resulting in formation of new blood vessels in the cardiac muscle tissue."
Clinical trials have demonstrated that bone marrow stem cells can generate new blood vessels in patients with ischemia of the legs, as well as patients with heart failure. One of the mechanisms by which bone marrow stem cells induce angiogenesis is through production of growth factors such as VEGF, FGF, and HGF.
Commercialization of stem cell therapies has various issues since the cells are alive and require very strict quality control and production systems. Accordingly, it is much more desirable from a financial perspective if the genes encoding the therapeutic factors made by stem cells can be directly delivered to an ischemic tissue in order to stimulate angiogenesis. Indeed this is occurring today. For example, the company AnGes has issued US patent 7285540, which covers the use of hepatocyte growth factor (HGF) for the stimulation of angiogenesis. US patent 6451303, assigned to Chiron, covers the use of FGF for stimulation of angiogenesis.
In a recent publication (Nikol et al. Therapeutic Angiogenesis With Intramuscular NV1FGF Improves Amputation-free Survival in Patients With Critical Limb Ischemia. Mol Ther. 2008 Apr 1) clinical trial results are reported from patients with critical limb ischemia that recieved a gene therapy product encoding the FGF-1 gene.
This clinical study recruited 59 patients in the treatment group and 66 in the placebo control. Patients eligible for the study had to be forty five years of age or older, had to have critical limb ischemia with one or more ulcers present, and not eligible for surgical or percutaneous revascularization. Diagnosis of critical limb ischemia required verification of occlusion, either by Doppler or angiography, as well as resting toe pressure of equal to or less than 50 mmHg, ankle pressure of equal to or less than 70 mmHg, and/or TcP02 equal to or less than 20 mmHg and/or metatarsal pulse absent or barely detectable.
The patients were treated with 8 injections of the FGF-1 expressing plasmid on days 1, 15, 30, and 45. The injections comprised of 2.5 ml of fluid which contained a total of 0.5 mg of the plasmid. For each treatment the patients recieved 4 injections in the calf and four in the thigh. For the patients that had CLI in both legs, the leg which was most likely to improve was treated.
The results:
- Placebo and treated groups had similar rate of ulcer healing: treatment 19.6%, placebo 14.3%.
- Statistically significant (approximately 2-fold) reduced risk of amputation in patients in the treatment group
- Trend for less risk of death in the treated group
- High number of adverse events for both placebo and treated groups
- Gene transfer was well tolerated
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