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Targeted Delivery of Oligonucleotides: Tissue-specific Challenges and Novel Conjugation

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At TIDES USA 2021, the latest challenges and learnings in targeted delivery of oligonucleotides were discussed by a panel of industry experts, including novel conjugation strategies. Biotech writer David Orchard-Webb picks the key takeaways.

Patisiran was approved in 2018 by the US Food and Drug Administration (FDA), officially the first siRNA oligonucleotide to reach the market, some three years ago. It targets the liver.

Others in the field have achieved notable successes with oligonucleotides, however the following quote, referenced by the chair, Muthiah (Mano) Manoharan, PhD, Senior Vice President of Drug Discovery at Alnylam Pharmaceuticals, Inc., appeared to resonate with many on the panel:

“This is not the end, this is not even the beginning of the end, this is just perhaps the end of the beginning” - Winston Churchill

Each member of the panel gave a short presentation which was followed by a group discussion on the targeted delivery of oligonucleotides, tissue-specific challenges and novel conjugation.

This is an extract taken from the ebook Delivery Systems and Strategies for Oligonucleotide Therapeutics. Read the full ebook here.

Moving Beyond the Liver

Given the initial difficulties in the field regarding oligonucleotide stability and systemic delivery, the successful strategies to date have focused on targeting the liver.

Alnylam found that liver delivery was enabled phospho-pyruvates for antisense oligonucleotides and aided by the lipid nanoparticles (LNPs) or by N-Acetylgalactosamine (GalNAc) conjugates for siRNAs and these are the two reference platforms.

LNPs now start from the small oligonucleotides, and all the way to mRNA vaccines, including those targeting SARS-CoV-2.

Alnylam have started looking beyond the liver, they wanted to go into all tissues and all cell types. According to Dr. Manoharan, the billion-dollar problems of delivery are endosomolytic release, oral delivery of oligonucleotides, and blood-brain-barrier penetration.

On the challenge of endosomal release, Dr. Manoharan noted that there has been little improvement in the efficiency over that achieved 30 years ago, so he reiterated Jean-Paul Behr’s conclusion from that time; “Chemists, back to the bench!”

Building The Antibody-Receptor Repertoire

On the subject of endosomal release, Arthur (Art) Levin PhD, Chief Scientific Officer at Avidity Biosciences, Inc. agreed; “we have nanomolar concentrations of drugs in cells with our technology and we know that our therapeutic agents are active at the picomolar range”, the implication being that most of the drug is trapped in the endosomes.

The main subject of his talk, however, was receptor mediated uptake. Echoing Oxana Beskrovnaya’s FORCE strategy, and Punit Seth’s comments later in this session, Dr. Levin said “of course, one of the more well-known transporters that we thought we could take advantage of is the transferrin receptor (TfR1)."

Dr. Levin favored an antibody approach to screening for useful receptors that can mediate uptake, because the asialoglycoprotein receptor seems to be the exception, rather than the norm.

Most cell surface receptors do not have high affinity ligands like GalNAc.

Therefore, Dr. Levin and Avidity is concentrating on oligonucleotides conjugated to monoclonal antibodies and trying to answer the question: “which ones work the best and why do they work the best?”

According to Dr. Levin, they have already discovered around a dozen cell-surface markers that can be targeted by antibodies to successfully deliver their oligonucleotide therapeutics into cells and tissues.

Using TfR1, right now they have specificity for skeletal and cardiac muscle. They continue to ask the question: can a receptor be found for just cardiac or just for skeletal, or other cell types that are of interest? Avidity’s goal is to continue the mining effort and to find other receptors.

In addition; their technology is scalable, they have hundreds of antibody-oligo conjugates.

They have demonstrated pharmacology with multiple different kinds of siRNAs and oligonucleotides Further, they have been able to demonstrate their concept across multiple species including non-human primates.

This is an extract taken from the ebook Delivery Systems and Strategies for Oligonucleotide Therapeutics. Read the full ebook here.

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