Developing Next Generation Oligonucleotide Therapeutics
Shalini Andersson, PhD; Vice President of Oligonucleotide Discovery, AstraZeneca
Oligonucleotides could treat “un-druggable” diseases, but the challenge of developing such therapies and turning them into deliverable, effective products should not be underestimated, according to Shalini Andersson, Ph.D., vice president of oligonucleotide discovery at AstraZeneca.
Andersson told delegates at the TIDES Asia conference that in essence oligonucleotides offer healthcare professionals a versatile way of treating a huge range of diseases.
“In many of the diseases that we’re struggling with, either you have too little protein or you have too much due to some disease setting,” Andersson said, adding “Oligonucleotides can regulate the mRNA that is producing the disease-causing protein.
“The good thing about nucleotide therapeutics is that these molecules are pretty versatile. They can have quite a broad application of different modes of actions, and you can use them for modulating quite a few different pathways and modes of actions.”
To date, only a handful of oligonucleotide-based drugs have been approved. However, Andersson predicted advances in the field will soon see more products brought to market, particularly in areas like rare disease treatment.
“It’s all about understanding what it is you want to modulate with your oligonucleotide, and this is also reflected a bit in the drugs that we have on the market today already,” she said.
“You have quite a lot of these molecules in the clinical phases now, and I would imagine that this will just accelerate going forward because we are understanding more the versatility and the type of patients and diseases that we can modulate with these kind of molecules.”
Challenges
Despite this potential, developing oligonucleotide therapies is not the easier option. These molecules are large, fragile, and carry a polar charge, which makes it hard to manufacture.
And although solving these problems has been a major focus for industry, optimizing oligonucleotides is still a challenge, according to Andersson.
“There were quite a few academic groups, some biotechs, who have actually stuck it out and sorted out some of the problems,” she said, citing Ionis as “one of those players who have helped us all understand what’s required to turn oligonucleotides into drugs.”
AstraZeneca’s approach is to identify a target, make the corresponding oligo sequences, and then fine tune them by making changes in some positions, according to Andersson, who said, “All of that together can give you a pretty optimized oligonucleotide that is a drug.”
AstraZeneca is also using artificial intelligence, specifically machine learning, to develop oligonucleotides with therapeutic potential.
“We have been able to see that by using machine learning, we can also improve the quality of the hits that we generate, which is something that I think will be much more of part of the drug discovery process going forward,” she said.
Oligo Targeting
Targeting is another ongoing challenge for the oligonucleotide sector, according to Andersson, particularly if the target is expressed in tissues where oligos do not normally go.“You need to get these molecules inside the cells to be able to modulate the RNA molecule that you’re trying to modulate or block. There is a big effort to develop targeted delivery approaches or enhanced uptake methods that allow your molecule to get into the cells,” she said.
“It is a challenge because you have to really find ways of reaching all the different tissues that you might be interested in to actually modulate some of the really difficult diseases that we’re not able to treat today.”
Many industry efforts to target oligonucleotides are focused on adding lipids to the molecules using linker technologies. However, even with this approach there are challenges, according to Andersson.
“You have to design your linker, your targeting ligand, the whole concept is like developing several drugs in one … and many people maybe do not appreciate how difficult a task that is. If it had been easy guys, everybody would have sorted this out a long time ago because there’s been a lot of effort into it.”
Andersson cited GalNAc, a sugar molecule that can binds a surface protein found on liver cells, as an example of an effective delivery technology “GalNAc is the gold standard that has been in the industry and has really shown the power of targeted delivery … by using GalNAc conjugation … we have been able to open up liver hepatocyte targets and have been able to modulate them,” she said.
Through enhanced targeting, the GalNAc technology allows you to lower the dose such that you can improve your safety margins, according to Andersson. “You can have a cost of goods case that is amenable to actually delivering drugs to people who are in need.”
Lipid-based targeting technologies are also showing promise, according to Andersson, who cited research by Annabelle Biscans at the RNA Institute in Boston as an example.
“They have shown that bio distribution of oligonucleotides can be changed on conjugation to lipids, and it will change in accordance with the lipophilicity of the fatty acid or the lipid. And so the more lipophilic you are, the more hydrophobic you are, the more of your oligo and ends up in the liver.“So you can play around with the hydrophobicity of the lipid to try to modulate where you want to go. And then they are also, it’s not just the liver and the kidney, it can also impact how much of the molecule or your drug you get into other tissues,” she said.
Andersson predicted that through such efforts the oligonucleotide sector will “start developing drugs for patients who have not had any possibilities to be treated before or have very low levels of treatment.And so that is something to think about.”