In an exclusive interview with BioPharma APAC, Arron Tolley, Chief Technology Officer of Aptamer Group, shares insights on the company's latest collaboration with AstraZeneca. This partnership aims to evaluate the potential of Optimer technology as non-viral vectors for siRNA delivery, specifically targeting fibrotic liver disease. Tolley outlines the key milestones, advantages of the Optimer platform over traditional methods, and the implications of successful demonstrations in animal models for the future of precision medicine. With a focus on enhancing targeted delivery and minimizing off-target effects, this collaboration represents a significant step forward in the development of innovative therapeutic solutions for underserved patient populations.

What are the key milestones that Aptamer Group aims to achieve in the next phase of this collaboration with AstraZeneca?

We’re delighted to be working with AstraZeneca on this new collaboration to evaluate Optimer as non-viral vectors for siRNA. It’s great to see large pharma partners evaluating our technology for its potential in siRNA delivery to specific cell types. 

As part of this collaboration, we will use our developed Optimer delivery vehicles specific to activated hepatic stellate cells (HSCs), the cells responsible for fibrotic liver disease, as a model vector for AstraZeneca’s siRNA molecule. Firstly, this will involve manufacture of the Optimer vector linked to AstraZeneca’s siRNA. Then, using the Optimer-siRNA we aim to demonstrate selective delivery to activated hepatic stellate cells along with significant gene knockdown. Starting with in vitro experiments to optimise the system and demonstrate performance, we then aim to move to in vivo experiments that will examine the localisation and gene silencing within an animal model. 

Assessment of Optimer functionality as delivery vehicles within animal models is the next step for Aptamer Group to demonstrate the performance of our fibrotic liver targeting Optimers. Reaching this stage of development will significantly derisk both this specific vector for liver disease and the platform technology as a whole for many of our partners.

Can you elaborate on the specific advantages of the Optimer technology over traditional delivery methods for siRNA?

Targeted delivery remains a significant challenge across the field of siRNA therapies, with three major hurdles:

(1) targeting the therapy to the specific cell type and reducing its interaction with non-target cells,

(2) getting the RNA therapy into the target cell and

(3) ensuring the RNA therapy is not trapped within the endosome once internalised, so that it is free to function.

GalNAc is a major molecule used in targeting therapies to the liver, which has proven very successful. It has been used for siRNA delivery in multiple approved therapies. However, GalNAc targets hepatocytes, which are the metabolic cells within the liver, and not activated HSCs like our Optimer, and so in this case the fibrotic liver Optimer allows us to target therapies for a different range of liver diseases. 

The important feature of the Optimer platform here is that we can use the same approach to develop delivery vehicles for different target tissues and cell types to support new precision therapies. In contrast, GalNAc is not immediately applicable to new cells in this way.  

Other siRNA delivery approaches currently in the clinic, with good success to date, are using antibodies as a targeting vehicle to muscle tissue. While Optimer is a direct antibody alternative, there are benefits of Optimer in terms of smaller size for improved tissue penetration and getting therapies deeper into tissues, particularly for dense tissues like fibrotic tissues and solid tumours. Also, for Optimer, our partners consider the faster development, highly controlled payload conjugation and tuneable specificity to be important advantages. 

How does Aptamer Group plan to address potential challenges in achieving successful cell internalisation of siRNA with the Optimer delivery vehicle?

We have already shown, using the developed Optimer delivery vehicle to fibrotic liver cells, that these Optimers deliver functional siRNA to the target cells with no interaction with other cell types of the liver. 

As mentioned Optimer can cross the cell membrane through multiple mechanisms, such as pinocytosis or receptor-mediated endocytosis, so internalisation into target cells can be achieved. During our development processes, we can specifically select for Optimer candidates that internalise into the target cell, so if we know that we need an Optimer to deliver therapeutic cargo into the cell we can account for this, and reject any Optimer candidates in the discovery process that do not allow cell penetration or that penetrate alternative cell types. 

Meeting these criteria at the early discovery stages can save time and costs downstream, ensuring the selectivity and functionality of our delivery vehicles to prevent further engineering. 

What initial results have been observed with the fibrotic liver delivery vehicles that prompted this new agreement with AstraZeneca?

Over the past year, we have progressed our work on the Optimer delivery vehicle for fibrotic liver as our initial model delivery vehicle for the Optimer platform. We will use this delivery vehicle in the new collaboration with AstraZeneca. Our in vitro dataset shows that the Optimer targets siRNA to the specific cell type, showing minimal off-target interactions across a panel of other cell types. The Optimer-siRNA can penetrate the target cells and achieve significant gene silencing with a dose-dependent response. 

Based on these results, AstraZeneca initiated the new agreement to trial this delivery vehicle with their siRNA and support us in advancing this to animal studies. 

Could you provide more details on the in-house experimental work Aptamer Group will conduct to assess the effectiveness of the Optimer-based delivery vehicle?

There will be multiple stages to our collaboration with AstraZeneca, some of which will be carried out in-house at Aptamer Group and some which will take place within partner labs. 

The initial stages will assess the performance of the siRNA to silence the genes within activated HSCs. Once we have this baseline, we will generate Optimer-siRNA conjugates using AstraZeneca’s siRNA. As part of this, we can assess multiple linker types and conjugation methods to optimise the Optimer-siRNA conjugate. 

The Optimer-siRNA conjugate will be tested in-house at Aptamer Group to evaluate selective delivery to activated HSCs and ensure minimal delivery to other off-target cell types of the liver. We will also assess the potential of the Optimer-siRNA to achieve significant gene silencing in the target cells. 

Following the optimisation of the Optimer-siRNA in lab-based tests, the intention of the partnership is to advance to animal studies to evaluate the conjugate’s performance in targeting and silencing in vivo. However, we will not carry out the animal work in-house, as we do not have any animals on-site at Aptamer Group, and we work using wholly animal-free methods to discover and develop our Optimer binders. 

As this partnership progresses, it will demonstrate the ability of the Optimer delivery vehicle to meet all three of the major challenges in the targeted delivery of siRNA through cell selectivity, internalisation, and delivery of a functional payload. AstraZeneca is interested in evaluating the data produced across these in vitro and in vivo experiments to gain further insight into our Optimer platform, and working together in this way, means that Aptamer Group can make rapid progress in this area. 

What are the implications of a successful demonstration in animal models for the future development and commercialization of Optimer-enabled siRNA delivery systems?

The demonstration of Optimer-enabled siRNA delivery in animal models is a key milestone in derisking the fibrotic liver Optimer delivery vehicle and the Optimer platform as a whole for generating further delivery vehicles. We have many partners interested in the performance of Optimer delivery vehicles in animal models. This data could encourage the adoption of the Optimer platform as a new delivery system across the field of precision medicines.  

As the primary route through preclinical trials for any new therapy is through demonstration in animal models, showing this level of performance in the Optimer platform will validate the platform and help increase the licensing potential of the fibrotic liver Optimer delivery vehicle. 

We’re excited to collaborate with large pharma partners, like AstraZeneca, to support us moving to this next stage in the development of Optimer delivery vehicles.