Takematsu Eri, Massidda Miles, Howe Gretchen, Goldman Julia, Felli Patricia, Mei Lei, Callahan Gregory, Sligar Andrew D, Smalling Richard, Baker Aaron B
bioRxiv. 2023 Mar 23:2023.03.20.533550. doi: 10.1101/2023.03.20.533550.
Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.
使缺血组织血管再生的疗法长期以来一直是治疗血管疾病和其他病症的目标。使用干细胞因子（SCF，也称为c-Kit配体）的疗法在治疗心肌梗死和中风的缺血方面具有很大前景，然而，由于包括患者体内肥大细胞激活在内的毒副作用，SCF的临床开发被停止。我们最近开发了一种新型疗法，使用脂质纳米盘递送的跨膜形式的SCF（tmSCF）。在先前的研究中，我们证明tmSCF纳米盘能够诱导小鼠缺血肢体的血管再生，并且不会激活肥大细胞。为了将这种疗法推进到临床应用，我们在患有高脂血症和糖尿病的兔后肢缺血的高级模型中测试了这种疗法。该模型对血管生成疗法具有治疗抗性，并且在从缺血性损伤恢复方面长期存在缺陷。我们用tmSCF纳米盘或从藻酸盐凝胶局部递送至兔缺血肢体的对照溶液对兔进行局部治疗。八周后，通过血管造影定量分析，我们发现与藻酸盐治疗的对照组相比，tmSCF纳米盘治疗组的血管生成明显更高。组织学分析还显示，tmSCF纳米盘治疗组缺血肌肉中小血管和大血管的数量明显更多。重要的是，我们在兔中未观察到炎症或肥大细胞激活。总体而言，这项研究支持tmSCF纳米盘治疗外周缺血的治疗潜力。
