Engineering brain-derived neurotrophic factor mRNA delivery for the treatment of Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) has a long history in the treatment neurodegenerative of diseases. However, this therapy has limitations in exogenous protein safety, including side effects like neuropathic pain and seizures. Moreover, there are currently no positive clinical trial results using BDNF-based gene therapy. Given this, new methods of delivering BDNF are urgently needed. Here, we report an engineering BDNF mRNA-based therapy in a murine model of Alzheimer's disease (AD). Two poly (beta amino esters) polymers (PBAE) were synthesized, which achieved mRNA delivery to brain and spinal cord efficiently following catheter ventricle pumping. To confer stability and RNase resistance, the secondary structure of the mRNA was engineering using AI algorithms. Further mRNA modification was done on 3 ' untranslated region (3'UTR), which was added with neuron-specific miRNA targeting sequence to avoid BDNF protein expression in neuron. This allowed reduced neuronal overexcitation and seizures. And BDNF protein was sustained released from astrocytes to maintain surrounding neural function. The engineering mRNA was delivered into the brain ventricle and translated into astrocytes to significantly improve the memory of AD mice. Given the mRNA modifications presented here, it would de-target delivery to specific cell types and has therapeutic potential for the treatment of neurological diseases.