Phase I study of multi-gene cell therapy in patients with peripheral artery disease

Grossman, Paul; Mohler, Emile R.; Roessler, Blake J.; Wilensky, Robert L.; Levine, Bruce L.; Woo, Edward Y.; Upchurch, Gilbert R.; Schneiderman, Jacob; Koren, Belly; Hutoran, Marina; Gershstein, Diana; Flugelman, Moshe Y.

doi:10.1177/1358863x15612148

Cited by 13 publications

(15 citation statements)

References 36 publications

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“…Average improvement in walking time was 70%; six patients showed a dramatic improvement in walking time, whereas the other six showed no change in walking time. 20 The use of proteins and gene therapy in CLI has thus far failed to demonstrate efficacy in large-scale controlled studies. There has been an attempt to use hepatocyte growth factor plasmid for CLI patients in a phase IIb study, but the results of this study are currently not available (ClinicalTrials.gov Identifier: NCT02016755).…”

Section: Discussionmentioning

confidence: 99%

“…In extensive preclinical studies we showed the ability of fully differentiated, modified vascular cells to produce arteriogenesis, and thus we proceeded to a phase I study in claudicants. 20 The use of fully differentiated cells enables their full characterization (Table 3). This contrasts with stem cells, which represent a heterogeneous cell population.…”

Section: Discussionmentioning

confidence: 99%

“…19 We also showed activation of multiple genes that participate in arteriogenesis after gene transfer to the fully differentiated venous cells. 20 Previously, we demonstrated the safety of MGA in 12 patients with limiting claudication; walking time and time to onset of pain improved. 20 The current open-label study investigated the safety of two dose levels of intra-arterial MGA injections in no-option CLI patients.…”

Section: Introductionmentioning

confidence: 93%

“…20 Previously, we demonstrated the safety of MGA in 12 patients with limiting claudication; walking time and time to onset of pain improved. 20 The current open-label study investigated the safety of two dose levels of intra-arterial MGA injections in no-option CLI patients. Secondary endpoints were the course of rest pain and the size of ulcers up to 1 year after MGA injections and the quality of life at 3 months post-treatment.…”

Section: Introductionmentioning

confidence: 93%

“…18 We developed MultiGeneAngio (MGA), which is a novel, autologous, cell-based therapy. 19,20 MGA contains transduced autologous venous smooth muscle cells (SMCs), which express vascular endothelial growth factor (VEGF 165 ), and autologous venous endothelial cells (ECs), which express Angiopoietin-1 (Ang-1). Co-expression of the genes encoding Ang-1 and VEGF 165 , in two distinct cell types, ensures the coordination of at least two elements fundamentally involved in the angiogenic response: EC and SMC.…”

Section: Introductionmentioning

confidence: 99%

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Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia

et al. 2017

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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 × 10 or 5 × 10 (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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia

et al. 2017

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Autologous cells derived from different sources and administered using different regimens for 'no-option' critical lower limb ischaemia patients

Fadilah

Ismail

Jamaludin

et al. 2018

Cochrane Database of Systematic Reviews

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Mostly low- and very low-quality evidence suggests no clear differences between different stem cell sources and different treatment regimens of autologous cell implantation for outcomes such as all-cause mortality, amputation rate, ulcer healing, and rest pain for 'no-option' CLI patients. Pooled analyses did not show a clear difference in clinical outcomes whether cells were administered via IM or IA routes. High-quality evidence is lacking; therefore the efficacy and long-term safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients, remain to be confirmed.Future RCTs with larger numbers of participants are needed to determine the efficacy of cell-based therapy for CLI patients, along with the optimal cell source, phenotype, dose, and route of implantation. Longer follow-up is needed to confirm the durability of angiogenic potential and the long-term safety of cell-based therapy.

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Gene Therapy for the Treatment of Chronic Wounds

García-Fuentes¹

2020

Therapeutic Dressings and Wound Healing Applications

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Phase I study of multi-gene cell therapy in patients with peripheral artery disease

Abstract: ClinicalTrials.gov Identifier: NCT00390767.

Cited by 13 publications

References 36 publications

Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia

Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia

Autologous cells derived from different sources and administered using different regimens for 'no-option' critical lower limb ischaemia patients

Gene Therapy for the Treatment of Chronic Wounds

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