Gene Therapy May Be Effective Atherosclerotic Treatment
One agent in phase-1 trials led to complete rest pain resolution in the majority of patients with chronic critical limb ischemia.
Potential gene therapies aimed at treating atherosclerosis include apolipoproteins and HIF-1α, according to Nicholas A.F. Chronos, MD, the Chief Medical and Scientific Officer at Saint Joseph’s Research Institute in Atlanta.
Gene therapy with apolipoprotein A-I Milano, also known as ETC-2126, shows promise, Chronos said. Apolipoprotein A-I is the major protein of HDL, which may promote reverse cholesterol transport. HDL has anti-inflammatory, antioxidant and antithrombotic actions and can correct vasodilation caused by endothelial dysfunction.
In a phase-2 clinical study in patients with acute coronary syndromes, weekly recombinant injections of ETC-216 induced rapid coronary atheroma regression after five weeks of therapy (Figure 1). Researchers randomized 57 patients with acute coronary syndromes to one of three treatments: placebo, 15 mg/kg of ETC-216, or 45 mg/kg of ETC-216. The safety profile was good, Chronos said.
The Milano gene therapy was also significantly more effective than the wild type gene for reducing atherosclerosis and plaque inflammation in a mouse model.
Another target
Another potential target is HIF-1α, which is “the master switch for hypoxic stress,” Chronos said.
HIF-1α affects cell survival, angiogenesis, vascular tone and iron/oxygen metabolism. It promotes recruitment of endothelial progenitor cells and is essential for myeloid cell-mediated inflammation.
This suggests, Chronos said, that transfection with a HIF-1α transgene may enhance an arteriogenic and an angiogenic response.
At six months, a majority of patients (12 of 23) with chronic critical limb ischemia had complete rest pain reduction at six months. At one year, the number increased to 14. Complete ulcer healing occurred in three patients at six months and in five patients at one year. More frequent observations of complete ulcer healing occurred at doses higher than 1 x 1010 vp dose among evaluable patients (Figure 2).
The safety profile of the transgene in a phase-1 trial indicated no serious adverse events. The majority of adverse events were injection site reactions, edema or mild-to-moderate leg pain.
Preclinical data
Preclinical studies indicated that overexpression of apoE led to regression of atherosclerosis, and human hepatic apoE gene transfer completely prevented atherosclerosis in mutant mice lacking native apoE expression.
Overexpression of MCP-1 had similar effects in other preclinical studies, attenuating atherosclerosis by inhibiting atherosclerotic formation and lesional macrophage accumulation, as well as stabilizing atheroma.
Trial interpretation
Cardiologists should be cautious, however, when interpreting gene therapy trials, Chronos said. Gene therapy carries the potential for adverse events. One rabbit model of urokinase-type plasminogen activator (uPA) demonstrated a seven- to 10-fold increase in uPA, but the therapy caused vasoconstriction and promoted atherosclerosis.
Gene therapy with vascular endothelial growth factor (VEGF) caused atherosclerosis in animal models; in clinical studies, however, local VEGF delivery did not worsen atherosclerosis.
Development, consequences
Atherosclerosis requires prolonged therapy to reduce lesion burden and reduced blood flow. It also requires acute treatments to dissolve or prevent thrombosis, Chronos said. The difficulty of identifying these treatments lies in the heterogeneity of the disease.
Cardiologists should remember that although they treat the end stages of the atherosclerotic process, the process begins early as monocytes permeate the endothelium and macrophages begin to engulf other cellular structures, Chronos said. The monocytes and macrophages are the underlying cells in subsequent thrombosis.
As atherosclerosis progresses, foam cells are generated and lipid cells accumulate, leading to eventual cell death. This often leads to vulnerable plaque that can result in an occlusive thrombus.