Hepatocyte growth factor to Improve Functioning in PAD: the HI-PAD Study

项目总结 我们和其他人的工作已经证实，患有下肢外周动脉的老年人 疾病(PAD)具有更大的功能损害、更快的功能衰退和更高的活动率 与没有PAD的人相比，损失更大。然而，几乎没有有效的药物疗法被确定为 改善PAD患者的下肢功能或预防功能下降。 VM202是编码肝细胞生长因子(HGF)两种异构体的含有cDNAs的表达载体。 VM202通过肌肉注射的方式注射到小腿肌肉中，在那里它局部产生HGF。HGF是一种 旁分泌细胞生长因子，刺激血管生成，促进骨骼肌再生，以及 提高自噬能力。PAD合并严重肢体缺血(CLI)患者的初步证据显示，HGF 改善踝臂指数(ABI)，这是衡量PAD严重程度的指标，并促进腿部溃疡 治愈。我们假设HGF的有利作用将改善PAD患者的行走能力。 没有CLI。 我们提出了一项试点双盲随机临床试验，以提供初步数据来解决我们的 双侧小牛骨骼肌注射VM202疗法改善下肢功能的假说 在患有PAD的老年人中，通过增加血管生成，改善小腿肌肉灌注，以及 促进小腿骨骼肌再生。参与者将是36名65岁及以上的PAD患者 没有CLI。 在我们的主要目标中，我们将确定PAD参与者是否随机分配到小腿骨骼肌 注射VM202后3个月的6分钟步行成绩有较大幅度的提高或较小的下降 随访，与那些随机注射安慰剂的小腿骨骼肌进行比较。在我们的第二目标中， 我们将确定随机分配到VM202的PAD参与者在跑步机上是否有更大的改善 步行能力、小腿骨骼肌灌注和小腿肌肉活检毛细血管密度的测量， 与安慰剂相比，骨骼肌再生和自噬。 如果我们的假设是正确的，结果将被用来设计一项大型的、确定的随机临床试验 VM202在数量庞大且数量不断增加的患者中改善下肢功能并防止行动不便 被PAD禁用且没有CLI的老年人。

PROJECT SUMMARY Our work and that of others has established that older people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and increased rates of mobility loss compared to people without PAD. However, few effective medical therapies have been identified for improving lower extremity functioning or preventing functional decline in people with PAD. VM202 is a plasmid that contains cDNA and encodes two isoforms of hepatocyte growth factor (HGF). VM202 is administered by intra-muscular injection into calf muscle where it locally produces HGF. HGF is a paracrine cellular growth factor that stimulates angiogenesis, promotes skeletal muscle regeneration, and improves autophagy. Preliminary evidence in PAD patients with critical limb ischemia (CLI) showed that HGF improved the ankle brachial index (ABI), a measure of PAD severity, and promoted lower extremity ulcer healing. We hypothesize that the favorable effects of HGF will improve walking performance in PAD patients without CLI. We propose a pilot double blinded randomized clinical trial to provide preliminary data to address our hypothesis that VM202 therapy, injected into calf skeletal muscle bilaterally, improves lower extremity functioning in older people with PAD, by increasing angiogenesis, improving calf muscle perfusion, and promoting calf skeletal muscle regeneration. Participants will be 36 people with PAD age 65 and older who do not have CLI. In our primary aim, we will determine whether PAD participants randomized to calf skeletal muscle injections of VM202 have greater increases or smaller declines in six-minute walk performance at 3-month follow-up, compared to those randomized to calf skeletal muscle injections of placebo. In our secondary aims, we will determine whether PAD participants randomized to VM202 have greater improvements in treadmill walking performance, calf skeletal muscle perfusion, and calf muscle biopsy measures of capillary density, skeletal muscle regeneration, and autophagy, compared to placebo. If our hypotheses are correct, results will be used to design a large, definitive randomized clinical trial of VM202 to improve lower extremity functioning and prevent mobility loss in the large and growing number of older people who are disabled by PAD and do not have CLI.