title: Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia.
abstract: Critical limb ischemia (CLI) is the most severe presentation of peripheral arterial disease. We developed cell-based therapy entailing intra-arterial injection of autologous venous endothelial cells (ECs) modified to express angiopoietin 1, combined with autologous venous smooth muscle cells (SMCs) modified to express vascular endothelial growth factor. This combination promoted arteriogenesis in animal models and was safe in patients with limiting claudication. In an open-label, phase Ib study, we assessed the safety and efficacy of this therapy in CLI patients who failed or were unsuitable for surgery or intravascular intervention. Of 23 patients enrolled, 18 with rest pain or non-healing ulcers (Rutherford categories 4 and 5) were treated according to protocol, and 5 with significant tissue loss (Rutherford 6) were treated under compassionate treatment. Patients were assigned randomly to receive 1 × 107or 5 × 107(EC-to-SMC ratio, 1:1) of the cell combination. One-year amputation-free survival rate was 72% (13/18) for Rutherford 4 and 5 patients; all 5 patients with Rutherford 6 underwent amputation. Of the 12 with unhealing ulcers at dosing, 6 had complete healing and 2 others had >66% reduction in ulcer size. Outcomes did not differ between the dose groups. No severe adverse events were observed related to the therapy.
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa 3436212, Israel; Rappaport Faculty of Medicine, Technion IIT, Haifa 3200003, Israel; VESSL Therapeutics Ltd., Haifa 3436212, Israel. Electronic address: myf@tx.technion.ac.il.
authors.forename: Moshe Y
authors.initials: MY
authors.lastname: Flugelman
authors.affiliation: Department of Vascular Surgery, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Halak
authors.affiliation: Department of General and Vascular Surgery, Barzilai Medical Center, Ashkelon 7830604, Israel; The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8499000, Israel.
authors.forename: Boris
authors.initials: B
authors.lastname: Yoffe
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Schneiderman
authors.affiliation: Departments of Vascular Surgery and Radiology, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Rubinstein
authors.affiliation: Departments of Vascular Surgery and Radiology, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: Allan-Isaac
authors.initials: AI
authors.lastname: Bloom
authors.affiliation: Department of Vascular Surgery, Kaplan Medical Center, Rehovot 76100, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Weinmann
authors.affiliation: Department of Vascular Surgery, Shaare Zedek Medical Center, Jerusalem 9103102, Israel.
authors.forename: Ilya
authors.initials: I
authors.lastname: Goldin
authors.affiliation: The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8499000, Israel; Department of Vascular Surgery, Soroka Medical Center, Beer-Sheva 8410101, Israel.
authors.forename: Victor
authors.initials: V
authors.lastname: Ginzburg
authors.affiliation: The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8499000, Israel; Department of Vascular Surgery, Soroka Medical Center, Beer-Sheva 8410101, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Mayzler
authors.affiliation: Rappaport Faculty of Medicine, Technion IIT, Haifa 3200003, Israel; Department of Vascular Surgery, Rambam Health Care Campus, Haifa 3109601, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Hoffman
authors.affiliation: VESSL Therapeutics Ltd., Haifa 3436212, Israel.
authors.forename: Belly
authors.initials: B
authors.lastname: Koren
authors.affiliation: VESSL Therapeutics Ltd., Haifa 3436212, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Gershtein
authors.affiliation: VESSL Therapeutics Ltd., Haifa 3436212, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Inbar
authors.affiliation: VESSL Therapeutics Ltd., Haifa 3436212, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Hutoran
authors.affiliation: Rappaport Faculty of Medicine, Technion IIT, Haifa 3200003, Israel; VESSL Therapeutics Ltd., Haifa 3436212, Israel.
authors.forename: Adili
authors.initials: A
authors.lastname: Tsaba
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000235:genetics*; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007511:Ischemia / Q000175:diagnosis / Q000209:etiology / Q000235:genetics* / Q000628:therapy*; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011788:Quality of Life; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D019076:Transgenes; D016896:Treatment Outcome
chemical_list: D042501:Angiogenic Proteins
keywords: Ang-1; VEGF; cell therapy; critical limb ischemia; gene therapy