Adjuvant of Gene Therapy Induces Neurodegeneration

On September 20th 2018, Cell Death & Disease published the research results of Liu Xingguo's research group from Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, “Polybrene induces neural degeneration by bidirectional Ca2+ influx-dependent mitochondrial and ER–mitochondrial dynamics”. 

Hexadimethrine bromide (Polybrene) Polybrene was widely used as a clinical drug at high doses for heparin neutralization or for promoting for viruses infection at lower doses. The further clinical usage as a heparin neutralizer was prohibited due to renal failure, while at lower does it is still used in research and even in clinical gene therapy. Since a low dose is used in those trails, the potential for toxicity has long been ignored. 

The Liu Xingguo research group found that after intracerebroventricular (ICV) polybrene injection, mice showed disability of movement accompanied neural death and gliosis in brain, and in human neurons, polybrene induces concentration-dependent neuritic beading and fragmentation. Mechanistically, polybrene induces a rapid voltage dependent calcium channel (VDCC)-mediated influx of extracellular Ca2+. The elevated cytoplasmic Ca2+ activates DRP1, which leads to mitochondrial fragmentation and metabolic dysfunction. At the same time, Ca2+ influx induces endoplasmic reticulum (ER) fragmentation and tightened associations between ER and mitochondria, which makes mitochondria prone to Ca2+ overloading and ensuing permeability transition. These results reveal an unexpected neuronal toxicity of polybrene, wherein Ca2+ influx serves as a regulator for both mitochondrial dynamics and ER-mitochondrial remodeling. 

This work was financially supported by The National Key Research and Development Program of China, Guangzhou regenerative medicine and health Guangdong laboratory, the National Natural Science Foundation projects of China, the foundation of Guangdong Province and Guangzhou city.