Delivery of mutant huntingtin-lowering antisense oligonucleotides to the brain by intranasally administered apolipoprotein A-I nanodisks

• Published in: Journal of controlled release Vol. 360; pp. 913 - 927
• Main Authors: Aly, Amirah E.-E., Caron, Nicholas S., Black, Hailey Findlay, Schmidt, Mandi E., Anderson, Christine, Ko, Seunghyun, Baddeley, Helen J.E., Anderson, Lisa, Casal, Lorenzo L., Rahavi, Reza S.M., Martin, Dale D.O., Hayden, Michael R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2023
• Subjects: Antisense oligonucleotide; Apolipoprotein; BBB; Huntington disease; Intranasal; Nanodisk; Non-invasive; BBB; Intranasal; Non-invasive; Huntington disease; Nanodisk; Apolipoprotein; Antisense oligonucleotide
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.07.027

Lowering mutant huntingtin (mHTT) in the central nervous system (CNS) using antisense oligonucleotides (ASOs) is a promising approach currently being evaluated in clinical trials for Huntington disease (HD). However, the therapeutic potential of ASOs in HD patients is limited by their inability to cross the blood-brain barrier (BBB). In non-human primates, intrathecal infusion of ASOs results in limited brain distribution, with higher ASO concentrations in superficial regions and lower concentrations in deeper regions, such as the basal ganglia. To address the need for improved delivery of ASOs to the brain, we are evaluating the therapeutic potential of apolipoprotein A-I nanodisks (apoA-I NDs) as novel delivery vehicles for mHTT-lowering ASOs to the CNS after intranasal administration. Here, we have demonstrated the ability of apoA-I nanodisks to bypass the BBB after intranasal delivery in the BACHD model of HD. Following intranasal administration of apoA-I NDs, apoA-I protein levels were elevated along the rostral-caudal brain axis, with highest levels in the most rostral brain regions including the olfactory bulb and frontal cortex. Double-label immunohistochemistry indicates that both the apoA-I and ASO deposit in neurons. Most importantly, a single intranasal dose of apoA-I ASO-NDs significantly reduces mHTT levels in the brain regions most affected in HD, namely the cortex and striatum. This approach represents a novel non-invasive means for improving delivery and brain distribution of oligonucleotide therapies and enhancing likelihood of efficacy. Improved ASO delivery to the brain has widespread application for treatment of many other CNS disorders. Intranasally-delivered apolipoprotein A-I nanodiscs (apoA-I NDs) successfully delivery antisense oligonucleotide to the brain and significantly reduce mutant huntingtin protein.(1)Huntington disease is characterized by accumulation of toxic mHTT in the brain, resulting in neurodegeneration.(2)When ASO alone is delivered intranasally, it may access the perivascular spaces in the brain but does not reduce mHTT levels in neurons.(3)After intranasal delivery, apoA-I ASO-NDs can be detected in many cells of the neurovascular unit, with highest levels in capillary endothelial cells and neurons, and results in significant reduction of mHTT levels in brain regions most affected in Huntington disease, the cortex and striatum. AC: astrocyte; ASO: antisense oligonucleotide; ASO-ND: apolipoprotein A-I ASO nanodisc; EC: endothelial cell; M: microglia; N: neuron; Nanodisc: apolipoprotein A-I nanodisc, PC: pericyte or perivascular macrophage. [Display omitted]