Taking an ‘upside-down’ approach to mRNA delivery

Ben Hargreaves speaks to Liberate Bio, a company that is hoping to address the delivery issues that could prevent mRNA, as well as siRNA and ASO therapeutics, from reaching their full potential.

The pandemic proved that mRNA technology could provide effective protection against infectious disease, at least in the case of COVID-19. Research into mRNA dates back to the 1970s, but with the approval of both Moderna and BioNTech/Pfizer’s vaccines, this approach has finally been validated. Once its potential as a means of stimulating an immune response had been established, attention quickly turned to where else the technology could provide a therapeutic solution.

The expectations for this therapeutic area are high, with Moderna, a leading company in the space, having a broad pipeline of potential therapies targeting oncology, regenerative therapeutics, hepatitis, and other therapeutic areas. At the end of last year, the UK government entered into a partnership with the company, which saw Moderna agree to provide 250 million vaccine doses per year over the course of a decade. In addition, the construction of a specialised manufacturing facility for mRNA vaccines was agreed. The UK government has one eye on the short-term, securing a supply of COVID-19 vaccines, but also towards future potential vaccines against the flu or other infectious diseases.

During the same month, Merck and Moderna released positive phase 2b results for their collaboration on a personalised vaccine targeting patients with melanoma, increasing the interest in the technology for areas wider than infectious disease. If such positive results can be translated into further commercial treatments, the level of investment funnelling into the technology will only increase, particularly from companies of the scale of Merck. However, to achieve the potential of the technology, there are still numerous challenges that need to be addressed. One study outlined the key areas that need to be overcome: the stability, immunogenicity, translation efficiency, and delivery of mRNA therapies. On the last point, there are already attempts to navigate the issue.

Why delivery is the challenge

As it stands, mRNA vaccines and therapeutics can only provide benefits if they can reach the living cells and be processed into protein. To achieve this, mRNA must cross several extracellular and intracellular barriers before arriving at the target cells. The extracellular barriers include the cell membrane, ion pumps and channels, and the presence of RNases in skin and blood, among other issues. The intracellular barriers include endosomal escape, RNA sensors, and endonucleases.

There are a variety of mRNA delivery methods that have been developed in an attempt to navigate the challenges, such as direct injection of naked mRNA, lipid-based carriers, polymers, and protein derivatives. Those COVID vaccines that have experienced success are based around lipid nanoparticle delivery.

A company that is working on advancing non-viral delivery technologies for nucleic acid therapeutics, such as mRNA, small interfering ribonucleic acid (siRNA), and antisense oligonucleotides (ASOs), is Liberate Bio. siRNA therapeutics have already been validated with four approvals in the area, Novartis receiving approval for inclisiran at the end of 2021. The same is true for the antisense therapeutic area, though the number of approvals across all three therapeutic areas is limited, as these approaches are still becoming established.

Stephen Scully, co-founder and head of operations and strategy at Liberate Bio, explained the different necessities of each therapy, in terms of delivery: “Smaller siRNA and ASO nucleic acid therapeutics can be chemically synthesised with modifications that impart increased nuclease stability and do not require encapsulation into nanoparticle delivery vehicles. Conjugation of targeting ligands such as GalNAc, transferrin receptor antibodies, and lipophilic moieties to siRNAs and ASO have facilitated delivery to liver, muscle, and CNS tissues, respectively, in preclinical or clinical studies.

“Larger mRNA-based therapeutics are synthesised by in vitro transcription, which is not amenable to extensive nucleotide modifications and thus have poor stability when administered into the body. Therefore, encapsulation into a nanoparticle is typically required for protection.”

Taking a different approach

Liberate Bio states that the use of non-viral delivery vectors has been limited to liver indications and vaccines thus far. Scully outlined that the reason that the liver is currently often targeted is due to the fact that the lipid nanoparticles used for delivery typically accumulate in the organ when administered systemically. He stated that this makes liver indications the ‘low-hanging fruit’ for genetic medicines companies that have focused their efforts on optimising nucleic cargos.

By contrast, Liberate is taking “an upside-down” approach, by focusing its efforts on developing nanoparticle delivery vehicles to access extra-hepatic tissues. In particular, Scully said, “Particularly, we are establishing a high-throughput, in vivo screening platform to screen diverse libraries of materials (e.g. lipids and polymers) and formulations that may impart a variety of tissue tropisms. We will also be implementing computational machine learning approaches to utilise datasets to inform design of new materials and compositions.”

Further, the company will also explore a targeted approach demonstrated with siRNA and ASO conjugation, where ligands conjugated on the surface of nanoparticles could drive tissue tropisms of mRNA therapeutics.

Building a base

When asked about the progress Liberate has made on this pathway, Scully stated that the company has focused primarily on building out its team. Liberate was founded this year in Boston, US, with seeding funds from Khosla Ventures.

In terms of the wider team, Scully outlined, “Founders include Michael Mitchell (UPenn), Ness Bermingham (Khosla Ventures, formerly Intellia & Triplet Therapeutics), and Stephen Scully (formerly Intellia & Triplet Therapeutics), who have diverse scientific and operational skill sets. We have hired approximately 10 people, including leads in key areas such as formulations, chemistry, computational sciences, and molecular biology, and which will be instrumental in developing our delivery platforms.”

Liberate Bio itself is still in the early phase of its journey, having completed several animal studies so far. However, with the nucleic acid therapeutics space expected to grow further into the future, the importance of the work of companies aiming to limit the challenges of delivery could be key. For Ness Bermingham and Khosla Ventures, which is backed by assets worth $15bn, it also represents a financial judgement that investing in such a company will allow a return equivalent to the potential for growth of the area.