pUDK-HGF Gene Therapy to Relieve CLI Rest Pain and Ulcer: A Phase II, Double-Blind, Randomized Placebo-Controlled Trial

Abstract

BackgroundCritical limb ischemia (CLI) has become a global problem. Less invasive therapy is needed. Hepatocyte growth factor (HGF) is one of the most potent angiogenic protein and the plasmid encoding human hepatocyte growth factor (HGF) is considered to be the most promising gene therapy for CLI. MethodsWe conducted a randomised, double-blind, placebo-controlled trial to assess the e cacy and safety of intramuscular injection of plasmid pUDK-HGF expressing HGF. Pain-at-rest patients and ulcer patients were enrolled as two cohorts and randomized to receive intramuscular injection of placebo or pUDK-HGF. E cacy assessments included pain scale, ulcer size, TBI, ABI, and TcPO 2 over 180 day. Safety analysis was based on the occurrence of adverse events. ResultsIn the pain-at-rest cohort, the proportion of patients with complete pain relief after receiving pUDK-HGF injections was signi cantly higher than that of the placebo group on day 180 (p = 0.0148). More responders with >50% pain reduction were also observed in the pUDK-HGF groups than in the placebo groups (p = 0.0168). In the ulcer cohort of patients, pUDK-HGF treatment tended to be superior to the placebo in the percentage of patients with both complete ulcer healing and >50% ulcer healing. No signi cant differences in the incidence of adverse events or serious adverse events were observed among the groups. ConclusionIntramuscular injection of pUDK-HGF is safe and can signi cantly reduce pain-at-rest and possibly promotes ulcer healing in CLI patients. The mid dose pUDK-HGF (6 mg) was the most e cacious, and is an appropriate dose for phase III clinical trial.

Novel Therapies for the Treatment of Neuropathic Pain: Potential and Pitfalls

“…The vector contains complementary DNA of the opioid receptor, which has to be inoculated into the rats’ primary afferent neurons, leading to an upregulation of opioid receptors in the DRG, which may last for up to 6 months [ 144 , 145 ]. Moreover, all these techniques are under preclinical trial, and have not yet been used in humans [ 146 , 147 ].…”

Recent developments in targets for ischemic foot disease

“…Twelve randomised controlled trials were identified published since 2017 that tested a range of medical and rehabilitation therapies in patients with CLTI (Table 2). [48][49][50][51][52][53][54][55][56][57][58][59] Women were under-represented, being between 0% and 38% of the enroled patients (Table 2), thus highlighting the unmet need of gender equality in this field. The interventions tested mainly aimed to promote angiogenesis or arteriogenesis using growth factors or stem cells, including plasmids designed to upregulate Hepatocyte growth factor (HGF) or SDF-1, umbilical cord blood platelet gel, bone marrow aspirates, mononuclear cells, mesenchymal stem cells and endothelial cell progenitors.…”

“…59 The other trials had small sample sizes ranging from 20 to 155 and were thus underpowered to test the outcome assessed (Table 2). [48][49][50][51][52][53][54][55][56][57] Accepting this limitation, some promising results were reported for HGF and a number of cell therapies (Table 2). Gu and colleagues tested a HGF plasmid within two cohorts with ischaemic rest pain (n = 119) or ischaemic ulceration (n = 121) at doses ranging between 4 and 8 mg. 48 The proportion of patients with diabetes was not reported.…”

Therapeutic angiogenesis-based strategy for peripheral artery disease

“…Generally, the introduction of genetic material into a host can be achieved by using non-viral vectors, such as plasmid DNA or viral vectors, such as adenovirus and Sendai virus 95 , 96 . Since the first clinical trial for VEGF was conducted in 1996, extensive studies have been performed to assess the effectiveness of other pro-angiogenic factors, such as HGF and FGF ( Table 1 ) 29 , 97 - 101 . Furthermore, many studies using other pro-angiogenic factors, such as angiogenic factor with G-patch and Forkhead-associated domain 1 (AGGF1), human telomerase reverse transcriptase (hTERT), and some microRNAs (miRNAs), also showed promising results in promoting angiogenesis in animal models 102 - 105 .…”

“…In China, another clinical trial for CLI was conducted using an intramuscular injection of plasmid encoding human HGF , pUDK-HGF. The results of its phase II trial in 2014 showed complete pain relief or pain reduction in patients with CLI 97 , prompting the recruitment of phase III clinical trial participants (China Clinical Trial Registry, unique identifier: CTR20181274). Several clinical trials involving the combination of human HGF isoforms are also being held.…”