10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb

Muona, Kirsi; Mäkinen, Kimmo; Hedman, Marja; Manninen, Hannu; Ylä‐Herttuala, Seppo

doi:10.1038/gt.2011.109

Cited by 74 publications

(49 citation statements)

References 36 publications

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“…Follow-up studies performed at 8 and 10 years after gene therapy in the peripheral and coronary ischemia studies, respectively, however indicated that there were no significant differences in mortality or incidence of major adverse events between the treatment groups. 53,54 A first-generation adenoviral vector is also at the basis of a recently initiated, gene therapy angiogenesis trial aimed at delivering VEGF-D to the ischemic myocardium. In particular, this Phase I, singleblinded, placebo-controlled study entails NOGA-mediated transendocardial injection of escalating doses of vector to patients with coronary heart disease with no other therapeutic options (trial KAT301; http://clinicaltrials.gov/show/NCT01002430).…”

Section: Clinical Use Of Vegfmentioning

confidence: 99%

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

2012

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Section: Clinical Use Of Vegfmentioning

confidence: 99%

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

2012

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“…Multiple small trials in gene transfer of angiogenic growth factors have included intramuscular injection of either fibroblast growth factor (FGF) [41], hepatocyte growth factor (HGF) [42], or vascular endothelial growth factor (VEGF) [43]. The majority of these studies have shown these treatments to be safe though results with regard to efficacy endpoints, such as wound healing, pain relief, and improvements in ABI or TBI, are mixed [44][45][46].…”

Section: Investigational Therapiesmentioning

confidence: 97%

Limb Ischemia: Cardiovascular Diagnosis and Management from Head to Toe

2015

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Peripheral arterial disease (PAD) affects an estimated 27 million people in Europe and North America. Limb ischemia, defined as ischemic rest pain, ischemic ulcerations, or ischemic gangrene, represents the most severe manifestation of PAD and is associated with significant cardiovascular and limb morbidity and mortality. Critical limb ischemia (CLI), defined as limb ischemia symptoms for greater than 2 weeks, is characterized by a cascade of hemodynamically significant macrovascular atherosclerotic obstruction and microvascular changes culminating in decreased muscle perfusion, disrupted muscle energy metabolism, and inflammation. In contrast, acute limb ischemia (ALI) is defined as limb ischemia symptoms characterized by sudden onset of less than 2 weeks duration resulting in hemodynamically compromised limb perfusion. Diagnosis of both ALI and CLI is dependent on history, physical examination, and a combination of anatomic and hemodynamic assessment of the limb. Given that the risk factors for ALI and CLI overlap with risk factors for atherosclerotic coronary and neurovascular disease, the management of limb ischemia is focused on both endovascular or surgical limb salvage and cardiovascular risk factor control. Despite advancements in endovascular and surgical revascularization techniques, limb morbidity remains high; clinical trials of angiogenic and cell-based therapies are ongoing. Cardiovascular risk reduction in patients with limb ischemia also remains suboptimal and future studies will focus on novel antiplatelet agents.

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“…Schratzberger et al partly reversed the development of reduced nerve conduction velocities and sensory nerve action potentials with a VEGF gene transfer in a rabbit ischemic peripheral neuropathy model and prevented the hypoxia-induced apoptosis of SCs in vitro [24]. However, in clinical trials, no great improvement was reported in nerve conduction velocities and despite the initial promise of gene therapy, there is still currently no treatment available that can effectively repair the damage induced by DPN [25-27]. Several traditional natural medicines have been found to relieve the symptoms of DPN through antioxidant properties and by inhibiting the apoptotic nature of SCs in hyperglycemic conditions [28, 29].…”

Section: Discussionmentioning

confidence: 99%

Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy

Tang

Chen

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: High glucose-induced oxidative stress and inflammatory responses play an important role in painful diabetic neuropathy by activating the TLR4/NFκB signal pathway. Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs provide a microenvironment favoring vascular regeneration but their low survival ratio in hyperglycemic conditions suppress the function to promote nerve growth. Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes remyelination after peripheral nerve injury. The aim of this study was to identify the role of Nrf2 in SC-mediated functional recovery after sciatic nerve injury. Methods: We compared plasma inflammatory factors in diabetic patients (DN) with/without diabetic peripheral neuropathy (DPN) and assessed whether Nrf2 expression in SCs could repair peripheral nerve injury in a rat model. Nrf2, TLR4/NFκB signal pathway and apoptosis relative protein expression were detected by western blot. Apoptosis and angiogenesis were determined by immunofluorescence and tubule formation assay, respectively. Regenerated nerves were determined by transmission electron microscope. Results: Higher levels of inflammatory factors and VEGF expression were found in DPN patients. Cellular experiments indicate that Nrf2 expression inhibits hyperglycemia-induced apoptosis and promotes angiogenesis by regulating the TLR4/NFκB signal pathway. Animal experiments show that nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum are restored with transplantation of SCs overexpressing Nrf2. Conclusions: Taken together, the high survival ratio of SCs in a DPN rat model indicates that overexpression of Nrf2 restores nerve injury.

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10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb

Cited by 74 publications

References 36 publications

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

Limb Ischemia: Cardiovascular Diagnosis and Management from Head to Toe

Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy

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