Every year, tens of millions of people around the world are at risk of losing limbs by amputation. These people can benefit from the innovative treatments described in the March issue of Nature (18, 328-2012).
According to the February report of the US Centers for Disease Control and Prevention, the rate of non-traumatic lower limb amputations in diabetic people fell by 65% between 1996 and 2008. However, despite early diagnosis of diseases and highly professional care, the likelihood of such disability in diabetic patients remains eight times higher than in the healthy population on average. This is partly due to the fact that the arteries of the limbs of diabetic patients are not only more prone to atherosclerotic plaques, but also undergo specific structural changes in their walls. Patients with progressive atherosclerosis develop another devastating pathological condition known as chronic lower limb ischemia (CLI).
Current methods of treating CLI are based on drugs that control blood pressure and blood sugar levels, as well as recommended lifestyle changes, such as quitting smoking, exercise, and a healthy duet. More radical CLI treatment options are surgeries: balloon dilatation, stenting, bypass. However, these methods are not always available. If the lesion is too severe, physicians resort to amputation of the affected limb.
Innovations in this area are implemented in both cell and gene technologies. For instance, Aastrom Biosciences, Michigan, is on the verge of launching the final stage of clinical trials of its cell therapy drug Ixmyelocel-T which will involve 600 patients with critical limb ischemia (CLI), the most severe form of chronic lower limb ischemia. Globally, this is the first time that a CLI therapy of this sort has reached phase 3 testing, according to Nature. Mark Greger, a cardiovascular specialist at Brigham and Women’s Hospital, Boston, calls “cell therapy the next frontier.” Preclinical evidence suggests that Ixmyelocel-T indirectly promotes blood vessel formation by inducing the secretion of cytokines and growth factors that reduce inflammation. This may help explain the product’s success, says Timothy Mayleben, CEO at Aastrom. “Blood flow is absolutely necessary, but it's not sufficient,” he says. “We have to deal with the inflammation as well.”
In 2011, the Ministry of Health and Social Development of Russia registered the world’s first gene therapy drug for the treatment of CLI, Neovasculgen. This event can be considered a true milestone in the history of the development of gene therapy for CLI. In the 1990s, researchers began investigating non-invasive treatments that could cause new blood vessels to form. Jeffrey Isner, a cardiologist at Tufts University, Boston, treated a 71-year-old woman with right leg ischemia by inserting a balloon coated with DNA plasmid containing a gene encoding for vascular endothelial growth factor (VEGF). The therapy promoted the growth of new blood vessels, a process known as angiogenesis, and improved blood flow in the affected limb (348 Lancet, 370-374, 1996).
Data accumulated over the subsequent ten years showed that gene therapy had an acceptable safety profile, but the effectiveness of the methods was not always the best. In 2009, in Cambridge, Massachusetts, Genzyme announced the results of a phase 3 trial of an adenovirus therapy designed to transfer the gene encoding for hypoxia-inducible factor 1α. The trial involved about 300 CLI patients in whom this therapy was able to reduce leg pain. A year later, the French company Sanofi which acquired Genzyme announced that its gene therapy based on a DNA plasmid encoding for fibroblast growth factor 1 had no significant effect on the number of deaths and amputations in a study conducted on more than 500 patients with CLI (377 Lancet, 1929-1937, 2011).
“CLI is a very severe condition,” says Douglas Losordo, a cardiologist heading Baxter Healthcare’s new therapeutic development department in Illinois. “Angiogenesis is a complex process. The treatments that focus on increasing the expression of a single gene may be too simplistic,” says Dr. Losordo. “Or, perhaps, researchers have not yet discovered the right vector or delivery method.” In any case, gene therapy research continues. Korean ViroMed and Ohio-based Juventas Therapeutics are developing gene therapy drugs in phase 2 clinical trials.
Nature notes that Neovasculgen, a therapeutic drug based on VEGF-containing plasmids, which was approved in Russia late last year, doubled pain-free walking distance in 75 people compared with 25 placebo patients in a phase 3 clinical trial. The company that developed and released the drug, Human Stem Cell Institute (HSCI), is currently planning to begin its clinical trials in other countries. “We see great opportunity for Neovasculgen in the EU, as well as the American and Asian markets,” says HSCI’s CEO Artur Isaev, adding that the company will follow up the trial participants for three years to determine whether the therapy reduces amputation rates in people with CLI.