BMD‐001, a nanoparticle containing miR‐485‐3p antisense oligonucleotide, blocks Alzheimer's disease progression

Background Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction, which affects more than 44 million people worldwide. Currently, there is no effective therapy for AD despite its increasing global incidence; thus, effective treatment strategies for AD are urgently needed. Method In a previous report, we confirmed that expression of miR‐485‐3p was increased in the brain tissues, CSF, and plasma exosomes of AD patients than in healthy controls. In addition, the therapeutic potential of downregulation of miR‐485‐3p was also shown in 5XFAD AD model mice. Based on this target validation, we developed a nanoparticle containing antisense oligonucleotide (ASO) targeting miR‐485‐3p, named BMD‐001, which has a high CNS‐targeting ability to cross the blood‐brain barrier (BBB). BMD‐001 was injected into 10‐month‐old 5XFAD mice by intravenous injection, once weekly for four weeks. Behavioral tests were performed at 11 months and their brain pathology was examined after 8‐week‐washout at 13 months. Result To evaluate in vivo pharmacokinetics of BMD‐001, the plasma levels of Cy5‐labeled ASO encapsulated in the nanoparticle were measured after intravenous injection along with a naked ASO without formulation of nanoparticle. The half‐life of the ASO in the nanoparticle was 93 min while that of the naked ASO was only 43 sec. Furthermore, we also observed that the brain accumulation of the fluorescent ASO in the nanoparticle was 64‐fold higher than the naked ASO and was maintained up to 16 hours, as monitored by in vivo imaging. After BMD‐001 injection, miR‐485‐3p expression was decreased in the brain tissue. We found that BMD‐001 enhanced Aβ clearance via phagocytosis of Aβ in vitro and in vivo. Furthermore, BMD‐001 reduced Aβ plaques, tau pathology, inflammasome, neuroinflammation, and cognitive decline in the 5XFAD mice. Conclusion Collectively, our findings suggest that BMD‐001 is delivered to the brain through the efficient BBB penetration. Furthermore, BMD‐001 can be a promising candidate for treatment of AD pathology and cognitive decline, establishing a new paradigm in the AD field.