Gene Therapy of Critical Limb Ischemia Enters Clinical Use
Authors: Seppo Ylä-Herttuala
Journal: Molecular Therapy (2019)

Critical limb ischemia is caused by atherosclerosis and occlusions in peripheral arteries. Decreased blood perfusion in the lower limbs is the main pathogenetic mechanism, often accompanied by chronic infections and tissue loss. For patients, quality of life is severely reduced because of low mobility, significant rest pain, and ulcerations. Current treatments are based on endovascular operations and bypass surgery, but these operations are not always possible in elderly subjects. Therefore, there is a clear need for new treatments for millions of patients suffering from critical limb ischemia worldwide. Critical limb ischemia has been the target of several gene and cell therapy approaches during the last 20 years, with little success.1Mäkinen K. Manninen H. Hedman M. Matsi P. Mussalo H. Alhava E. Ylä-Herttuala S. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study.Mol. Ther. 2002; 6: 127-133Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 2Morishita R. Aoki M. Hashiya N. Makino H. Yamasaki K. Azuma J. Sawa Y. Matsuda H. Kaneda Y. Ogihara T. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease.Hypertension. 2004; 44: 203-209Crossref PubMed Scopus (194) Google Scholar, 3Nikol S. Baumgartner I. Van Belle E. Diehm C. Visoná A. Capogrossi M.C. Ferreira-Maldent N. Gallino A. Graham Wyatt M. Dinesh Wijesinghe L. et al.Therapeutic Angiogenesis With Intramuscular NV1FGF Improves Amputation-free Survival in Patients With Critical Limb Ischemia.Mol. Ther. 2008; 16: 972-978Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar The multiple comorbidities experienced by critical limb ischemia patients have been considered the main reason for the poor results. In September 2019, the Japanese regulatory authorities granted conditional, time-limited approval for Collategene to treat ulcers in patients suffering from peripheral arterial disease. This first approval of a gene therapy in Japan was accompanied by a request for post-approval evaluation over the next 5 years. The product was developed by AnGes Inc. in collaboration with Mitsubishi Tanabe Pharma.4Suda H. Murakami A. Kaga T. Tomioka H. Morishita R. Beperminogene perplasmid for the treatment of critical limb ischemia.Expert Rev. Cardiovasc. Ther. 2014; 12: 1145-1156Crossref PubMed Scopus (15) Google Scholar Collategene gene therapy involves delivery of a plasmid expressing hepatocyte growth factor (HGF) that is introduced into the lower limb muscles with multiple injections, leading presumably to improved local blood flow and ulcer healing.5Powell R.J. Simons M. Mendelsohn F.O. Daniel G. Henry T.D. Koga M. Morishita R. Annex B.H. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia.Circulation. 2008; 118: 58-65Crossref PubMed Scopus (236) Google Scholar In this issue of Molecular Therapy, Gu at al.6Gu Y.A. Cui S. Wang Q. Liu C. Jin B. Guo W. Liu C. Chu T. Shu C. Zhang F. Han C. A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia.Mol. Ther. 2019; 27 (this issue): 2158-2165Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar report the results of a randomized, double-blind, placebo-controlled phase II study using HGF plasmid for the treatment of critical limb ischemia. In 197 treated patients, including a placebo group and three different doses, the authors report a significant reduction in pain severity at all doses and a high percentage of complete ulcer healing in the high-dose group. The results are encouraging, and the data independently support efficacy previously shown by Collategene plasmid treatment in humans. Gu at al.6Gu Y.A. Cui S. Wang Q. Liu C. Jin B. Guo W. Liu C. Chu T. Shu C. Zhang F. Han C. A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia.Mol. Ther. 2019; 27 (this issue): 2158-2165Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar claim that their improved results are likely due to a better treatment regimen aided by angiography-guided lower limb injections and an improved dosing scheme that also included multiple plasmid injections administered at 0, 14, and 28 days, with the highest dose containing 24 mg of the HGF plasmid. No major safety issues were reported, although multiple injections caused injection-site irritation in all study groups. While encouraging, some questions remain open regarding the proposed proangiogenic mechanism of HGF since no significant differences in transcutaneous oxygen tension, angle-brachial index, or toe-brachial index were reported between the placebo and treatment groups. No changes in plasma HGF levels were detected, and no data were reported about possible angiographic findings or the expression of transgene, which would support increased angiogenesis and blood perfusion of the treated limbs. Since critical limb ischemia is a significant health problem worldwide, it is important that new approved products and confirmatory positive clinical results are reported from randomized, blinded, controlled studies. While some questions remain regarding the mechanistic aspects and feasibility of a multiple injection-based high dose plasmid regimen, this new report of HGF plasmid therapy gives new hope to those severely affected patients who cannot be treated with endovascular operations or with bypass surgery. A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Hepatocyte Growth Factor in the Treatment of Critical Limb IschemiaGu et al.Molecular TherapyOctober 31, 2019In BriefCritical limb ischemia is a disease causing rest pain and ulcer of limbs. In this issue of Molecular Therapy, Gu et al. present evidence demonstrating that NL003 was benefiting in phase II. It is suggested that NL003 has the potential to treat critical limb ischemia. Full-Text PDF Open Archive