Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy

Abstract

Antisense oligonucleotides (ASOs) have emerged as one of the most innovative new genetic drug modalities. However, their high molecular weight limits their bioavailability for otherwise treatable neurological disorders. We investigated conjugation of ASOs to an antibody against the murine transferrin receptor (TfR), 8D3130, and evaluated it via systemic administration in mouse models of the neurodegenerative disease, spinal muscular atrophy (SMA). SMA, like several other neurological and neuromuscular diseases, is treatable with single-stranded ASOs that modulate splicing of the survival motor neuron 2 (SMN2) gene.Administration of 8D3130-ASO conjugate resulted in elevated levels of bioavailability to the brain. Additionally, 8D3130-ASO yielded therapeutic levels of SMN2 splicing in the central nervous system of adult hSMN2 transgenic mice which resulted in extended survival of a severely affected SMA mouse model. Systemic delivery of nucleic acid therapies with brain targeting antibodies offers powerful translational potential for future treatments of neuromuscular and neurodegenerative diseases.

Preclinical Screening of Splice-Switching Antisense Oligonucleotides in PDAC Organoids

“…The method described herein should be compatible with other advances in antisense technology. For example, conjugation with antibodies (27), GalNAc (28), or aptamers (29) might enhance ASO delivery in organoids. Lead ASOs identified using our method can be optimized by subsequent conjugation of various ligands to enhance delivery to target tissues.…”

Revival of Bioengineered Proteins as Carriers for Nucleic Acids

“…One of the most straightforward nucleic acid delivery methods is through antibody-oligonucleotide conjugates (AOCs). The simplicity of AOCs makes them readily adaptable, while the pool of available antibodies continuously expands. , Since 2022, various AOCs entered phase 2 clinical trials for a variety of indications, such as myotonic dystrophy type 1. , The principle of targeting carriers via antibodies and receptor-specific peptides is not limited to the delivery of oligonucleotides. Incorporation of these targeting moieties also showed increased cellular uptake and cell specificity for protein-based DNA and mRNA carriers. − To enable cytoplasmic delivery multiple studies exploited the ability of pore-forming proteins to connect the endosomal lumen to the cytosol. ,, For example, Wittrup et al, employed pore-forming perfringolysin O (PFO) as a potent endosomal escape agent in their protein-based siRNA carrier .…”

“…The simplicity of AOCs makes them readily adaptable, while the pool of available antibodies continuously expands. 56,57 Since 2022, various AOCs entered phase 2 clinical trials for a variety of indications, such as myotonic dystrophy type 1. 58,59 The principle of targeting carriers via antibodies and receptor-specific peptides is not limited to the delivery of oligonucleotides.…”

An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery

“…We chose TfR1 as a target because of its high expression on the human BBB; its ability to mediate constitutive, ligand-independent receptor-mediated transcytosis (RMT) across the CNS vasculature (8)(9)(10)(11)(12); and its track record as a target to increase the delivery of biologics into the CNS of mice (13)(14)(15), nonhuman primates (NHPs) (16)(17)(18), and humans as investigational therapies (19)(20)(21)(22) and as an approved antibody-based therapeutic for Mucopolysaccharidosis type II (23). We first screened 7-mer-modified AAV9 capsid libraries for their ability to bind to human TfR1 in vitro.…”