From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.),
Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St
Elizabeth's Medical Center, Tufts University School of Medicine, Boston,
Mass.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center of Boston, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu
Background—Preclinical studies have
indicated that angiogenic growth factors can stimulate the development
of collateral arteries, a concept called "therapeutic
angiogenesis." The objectives of this phase 1 clinical trial were (1)
to document the safety and feasibility of intramuscular gene transfer
by use of naked plasmid DNA encoding an endothelial
cell mitogen and (2) to analyze potential therapeutic benefits
in patients with critical limb ischemia.
Methods and Results—Gene transfer was performed in 10 limbs of 9
patients with nonhealing ischemic ulcers (n=7/10) and/or rest
pain (n=10/10) due to peripheral arterial
disease. A total dose of 4000 µg of naked plasmid DNA encoding the
165-amino-acid isoform of human vascular endothelial
growth factor (phVEGF165) was injected directly into the
muscles of the ischemic limb. Gene expression was documented by
a transient increase in serum levels of VEGF monitored by ELISA. The
ankle-brachial index improved significantly (0.33±0.05 to 0.48±0.03,
P=.02); newly visible collateral blood vessels were
directly documented by contrast angiography in 7 limbs; and magnetic
resonance angiography showed qualitative evidence of improved distal
flow in 8 limbs. Ischemic ulcers healed or markedly improved in
4 of 7 limbs, including successful limb salvage in 3 patients
recommended for below-knee amputation. Tissue specimens obtained from
an amputee 10 weeks after gene therapy showed foci of proliferating
endothelial cells by immunohistochemistry. PCR and
Southern blot analyses indicated persistence of small amounts
of plasmid DNA. Complications were limited to transient lower-extremity
edema in 6 patients, consistent with VEGF enhancement of
vascular permeability.
Conclusions—These findings may be cautiously interpreted to
indicate that intramuscular injection of naked plasmid DNA achieves
constitutive overexpression of VEGF sufficient to induce therapeutic
angiogenesis in selected patients with critical limb ischemia.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Constitutive Expression of phVEGF165 After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia
Key Words: angiogenesis • genes • ischemia • growth substances
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