Safety Study of Gene Therapy in Treating Lower Leg Ischemia

Inclusion Criteria:

• Male or female, between 20 and 90 years of age

• Have critical limb ischemia (Rutherford Class 4 and 5) and considered not a candidate for bypass graft surgery or percutaneous angioplasty due to comorbid conditions, failure of previous surgical or interventional procedures or caliber of grafting arteries. Critical Limb ischemia is defined as

  1. Stable symptoms on standard therapy including anti-platelet agents, vascular rheologic agents, cilostazol, anticoagulant and pain medication for 30 days.
  2. Pain at rest and/or ischemic ulcers for a minimum of 4 weeks.
• Have diagnostic angiography of the affected limb in the last 12 months demonstrating a significant occlusion of one more of the following arteries: iliac, superficial femoral, popliteal, and one or more infra-popliteal arteries.
• Have a resting ankle systolic pressure (in either the dorsalis pedis or posterior tibial arteries) of less than or equal to 60mmHg or a resting toe systolic pressure of less than or equal to 40 mmHg in the affected limb.
• Be willing to maintain current drug therapy for peripheral arterial disease throughout the course of the study including anti-platelet and statin (CoA Reductase) inhibitor treatment
• Be capable of understanding and complying with the protocol and signing the informed consent document prior to being subjected to any study related procedures
• Women who are surgically sterile or at least 1 year postmenopausal or who have been practicing adequate contraception for at least 12 weeks prior to entering the study. If the subject is of child-bearing potential, she must have a negative serum pregnancy test result during the study.
• If the subject or the subject's partner(s) is of child bearing potential, the subject and the subject's partner(s) must agree to use a "double barrier" method of birth control while participating in this study.

Exclusion Criteria:

• Subjects who have undergone a revascularization procedure or sympathectomy within 12 weeks prior to study entry that remains patent. A failed revascularization procedure in the previous 4 weeks is acceptable.
• Subjects with grade 3 (hemorrhages, exudates) or grade 4 (papilledema) retinopathy.
• Subjects currently receiving immunosuppressive medications, chemotherapy, radiation therapy.
• Subject with aorto-iliac occlusion (greater than 75%).
• Subjects that will require amputation within 4 weeks of randomization.
• Subjects with any co-morbid conditions likely to interfere with assessment of safety or efficacy or with an estimated life expectancy of less than 6 months
• Subjects with history of drug (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 3 months.
• Subjects with a current history or new screening finding of malignant neoplasm except for basal cell carcinoma of the skin and squamous cell carcinoma of the skin (if excised and no evidence of recurrence).
• Subjects with evidence of active infection (e.g. cellulitis, osteomyelitis) or deep ulceration exposing bone or tendon in the extremity planned for treatment.

• Subjects with a clinically significant abnormality in routine hematology, urinalysis, chemistry, liver function or other laboratory tests, including HIV, Hepatitis B (HepBSAg), Cytomegalovirus (CMV), hepatitis C virus (HCV), Venereal Disease Research Laboratory test (VDRL), prostate-specific antigen (PSA), and chorio-embryonic antigen (CEA), or signs of malignant neoplasm by radiological imaging tests, including chest radiograph at Screening or Day 1. Specific laboratory exclusion criteria include the following:

  1. Hemoglobin less than 9.0 G/dl
  2. WBC count less than 3,000
  3. Platelet count less than 75,000
  4. Fasting glucose greater than 250 mg/dl
  5. AST and/or ALT greater than 3X upper limit of normal
• Subjects with any other condition that in the opinion of the investigator might put the subject at risk or interfere with his/her participation.
• Subjects unable or unwilling to comply with the protocol or to cooperate fully with the investigator or site personnel.
• Subjects that have received any other investigational drug within the 30 days prior to study drug administration or will receive such a drug during the timeframe of this study.
• Subjects with uncontrolled hypertension defined as systolic blood pressure greater than 200 mmHg or diastolic blood pressure greater than 115 mmHg at Baseline evaluation.
• Subjects with advanced liver disease including decompensated cirrhosis, jaundice, ascites or bleeding varices.