PDF(Pubmed)
Abstract：
Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.
摘要：
遗传性视网膜病是破坏性疾病，在大多数情况下缺乏治疗选择。由于在这些疾病中发现的突变的多样性,无论潜在的遗传损伤如何,减轻病理生理学的疾病修饰疗法是期望的。我们测试了一种基于系统药理学的策略，该策略使用坦索罗辛通过G蛋白偶联受体（GPCR）调节抑制细胞内cAMP和Ca2活性，美托洛尔,和溴隐亭联合用药。该治疗改善了Pde6βrd10和RhoP23H/WT色素性视网膜炎小鼠的视锥细胞功能并减缓变性。在PDE6A-/-狗中经过7个月的药物输注后，锥体变性得到适度缓解。该治疗还改善了Leber先天性黑蒙的Rpe65-/-小鼠模型中的杆通路功能，但不能防止视锥退化。RNA测序分析表明，药物治疗的Rpe65-/-和rd10小鼠的代谢功能得到改善。我们的数据表明，通过多种受体作用修饰第二信使水平的儿茶酚胺能GPCR药物组合提供了针对视网膜变性的潜在疾病修饰疗法。
