写的:
欧文·德·根斯特，
高级科学家，生物工程，R&D、澳门在线赌城娱乐
凯莉Foo,
卡罗林斯卡学院助理教授
Heart failure (HF) is a life-threatening disease that occurs when the heart cannot pump enough blood around the body. 它影响着全球6400万人，1 是导致死亡和住院的主要原因. The need for a therapy capable of addressing the root cause of cardiac dysfunction in HF remains high.
One of the characteristic signs of heart failure is defective calcium signalling. Calcium plays an integral role in the contraction and relaxation of the heart muscle.
During each heartbeat, intracellular calcium rises, leading to contraction of the muscle cell. 随后是钙的迅速减少, 这会导致放松, 准备让细胞产生下一次心跳.
The movement of calcium is facilitated by calcium-handling proteins on the surface of and inside cardiac cells which undergo complex dynamic transitions when they interact with other proteins.
Faulty interactions between calcium-handling proteins disrupt normal calcium signalling, 损害心脏肌肉收缩和放松的. This can potentially lead to dangerous heart arrythmias and structural changes, 最终可能导致心力衰竭和死亡.
Enhancing calcium cycling – and heart function - by blocking protein inhibitors
Sarco/内质网钙atp酶, 被称为“SERCA”是参与钙循环的关键蛋白质. It transports calcium from the cytosol to the sarcoplasmic reticulum where calcium is stored in cardiac muscles. The activity of SERCA is regulated by its interaction with phospholamban 或“PLN”，一种抑制心脏钙循环的蛋白质. 通过与SERCA结合, PLN controls the speed of calcium removal from the cytoplasm and the amount of calcium stored within the cell.
心力衰竭患者的SERCA水平往往较低, 以及相对较高的PLN水平, 导致活性SERCA分子过少. 这会导致心肌松弛缓慢和收缩乏力. 通过阻断或破坏PLN来促进钙循环, 因此, 提高心脏泵血的能力.
VHH可破坏PLN的作用
Previously, attempts were made to disrupt the activity of PLN using small molecule drugs. 然而, this approach proved unsuccessful because PLN is flexible and exists in a dynamic equilibrium between different structural forms and lacks clearly defined, 其结构中可访问的“口袋”, 通常需要哪些药物分子才能有效.
然而，在澳门第一赌城在线娱乐最新的研究中，发表在 自然通讯, we have found a way to disrupt PLN ‒ using VHH intrabodies ‒ which are derived from the antigen recognition domain of naturally occurring camelid heavy chain antibodies.2
We identified potent VHHs from a synthetic library that bind to PLN and prevent PLN monomers from binding to SERCA, 增强其活动性. 把两份相同的录像带连在一起, we showed that these dimeric VHHs increase the activity of SERCA even further by increasing the levels of inactive PLN pentamers.
We then used chemically modified messenger RNA – synthetic messenger molecules with enhanced stability inside cells – to validate the effectiveness of the VHHs against PLN 在体外, 使用分离的活心脏细胞.
Findings showed that the VHH intrabody helped normal calcium cycling to resume, restoring proper pumping functionality to the heart in a mouse with heart failure.
AAV-delivered VHH intrabodies could lead to novel heart failure treatment
Delivering drugs using adeno-associated viruses (AAVs) was previously shown to be effective for the 在活的有机体内 细胞外生物治疗药物的递送, and so these platforms presented an opportunity to evaluate the delivery of intrabodies.
We used heart-targeted AAV vectors engineered to express VHHs under the control of a cardiomyocyte-specific promoter. AAV vectors for heart-targeted intrabody delivery enable tissue selective expression using systemic administration, 将非相关组织的损伤风险降至最低. Injection into preclinical models effectively expressed the intrabodies specifically in the heart, 在肝脏或其他肌肉组织中没有检测到.
This research shows that VHH intrabodies could open the door to potential new treatments for heart failure, particularly when combined with emerging virus-based or nucleic acid ‒ based drug delivery technologies ‒ and may ultimately bring us a step closer to stopping hearts from failing.
“这项工作显示了mRNA方法的实用性, 通常被视为“功能增益平台”, to quickly screen and identify nanobody and other 'loss of function' therapeutic candidates” said Kenneth R. 他是卡罗林斯卡医学院心血管研究教授.
