Treatment of chronic conditions is the new frontier for stem cell-derived therapies: Deep phenotyping and manufacturing scale-up key to opening clinic doors, say experts at TTP’s panel discussion 

We asked our panellists Dr Terri Gaskell, CTO at Rinri Therapeutics, and Dr Davide Danovi, Director of Cellular Phenotyping and Product Support at bit.bio, what it will take to progress stem cells into commercial therapies for chronic conditions. The discussion was hosted by​ Dr Stuart Lowe,​ TTP’s Head of Cell and Gene Therapy.

A growing number of companies are working to show that stem cells have what it takes to expand the regenerative medicine market. Induced pluripotent stem cells (iPSCs), discovered in 2006 and capable of differentiating into many cell types, in particular, have reignited the appetite for stem cell-based regenerative therapies.

Developers seeking to deliver cell therapies to patients must manage several risks, such as the availability of donor material, graft-versus-host disease, and cell storage and maintenance. Stem cell-derived products can mitigate these concerns by providing:

These benefits have made stem cells an attractive proposition as a versatile starting material for therapeutic development – albeit one requiring upfront supply chain development.

Stem-cell derived therapies addressing chronic conditions and complications are now entering Phase I/II clinical trials.

Examples of clinical-stage companies highlighted at the panel discussion included Neurona Therapeutics and Cynata Therapeutics. Neurona recently reported near freedom from seizure and memory improvements in the first epilepsy patients to receive its NRTX-1001 iPSC-derived product. Cynata is developing several iPSC-derived mesenchymal stem cell treatments, notably for diabetic foot ulcers.

And our panellists are representative of some of the many companies now developing such therapies.

Rinri Therapeutics is developing a first-in-class off-the-shelf allogenic regenerative cell therapy for sensorineural hearing loss (SNHL) based on auditory sensory cell progenitors which are derived using a developmentally informed approach called OSPREY™ (Otic Sensory Progenitor REgenerative therapY). Gaskell’s focus is to translate over a decade’s worth of academic and preclinical research into a product for neural forms of SNHL that can be tested in patients in clinical trials.

bit.bio on the other hand takes a platform approach, using its opti-ox™ technology to deterministically program entire cultures of stem cells into a precise cell identity with unprecedented consistency and at industrial scale. bit.bio recently announced that its most advanced therapeutic candidate is based on hepatocytes for the treatment of patients with acute liver failure, as well as an underlying pipeline with potential to address significant unmet need across metabolism and endocrinology, immunology and neurology.

The future success of regenerative stem cell therapies hinges on developing and optimising living and differentiating cells – inherently variable materials to handle – into products that can be manufactured with a consistent safety and efficacy profile.

Even manufacturing the volumes of cells needed for clinical trials can be a challenge for some chronic conditions, said Gaskell about the industry.

For cell therapy developers under pressure from investor milestones, the temptation to use highly manual, non-scalable manufacturing to reach first-in-human clinical trial ‘come-what-may’ may not serve the long-term needs of patients: “We all have to be conscious that we’re not just trying to get into a clinical trial. We’re actually trying to generate therapies that can go much further than that,” said Gaskell.

Consistent and scalable manufacturing are inherent to the company’s technology and will be integral to the success of therapies emerging from bit.bio’s iPSC platform. “As it has been said, manufacturing at scale is the holy grail in this sector”, commented Danovi.

But still, bringing these treatments to the clinic is a multi-year project, against a backdrop of evolving regulation and technology.

Cell characterisation is central to the long-term efforts at both Rinri and bit.bio.

Gaskell suggested that “a deep understanding of what these products are” will be key to pinpointing cell identity and contribution to therapeutic effect and demonstrating comparability when changes need to be made as the therapies are brought to market.

This may include changes to the manufacturing process and to the cell lines chosen to differentiate into the therapeutic product.

“Deep phenotyping may enable us to prove comparability further down the line, avoiding the need to go back around the development loop and enabling these products to make it through to the end,” she said.

Gaskell and Danovi both see promise in imaging, boosted by recent advances in AI and single cell transcriptomics to streamline cell characterisation.

“At bit.bio, we are in a unique position by having the possibility to follow our cells as they become a neuron or a muscle cell from an iPSC. Both from the imaging and the transcriptomics point of view, this is super interesting”, said Danovi.

These technologies can equally benefit from real-time analytics, keeping the manufacturing process on track. However, cautioned Gaskell, any assays developed to hit near-term development milestones, whether for in-line analytics or release quality control, do need to be appropriate and implementable in a GMP manufacturing setting.

Danovi added that the development of this characterisation capability could repay itself through discovery. “Once we know what a neuron looks like, we can build a pipeline to pick up a neuron in a ‘haystack’ of other cells”.

Stuart Lowe, Head of Cell and Gene Therapy at TTP added:

“At TTP, we have a long history in scaling unit operations and manufacturing processes. Success often hinges on planning for scalable manufacturing from the earliest stages of product development. So when our expert team is working to implement cellular bioprocessing and characterisation techniques for manufacturing, we are always thinking about how these scale. Whether it’s imaging, ‘omics, or other emerging modalities, for specialised equipment or in platforms, integration into scalable manufacturing workflows is key.”

Of course, beyond the characterisation and manufacturing challenges, cell therapy developers also need to get other fundamental decisions right, as both panellists and other participants discussed during the event.

These include, first, which stem cell types to work with and, second, how to maximise the chances that early clinical trials can demonstrate not only safety, but also preliminary signs of efficacy – crucial for unlocking additional investment.

Importantly, Prof. Pete Coffey, of UCL, pointed out that working with the MHRA, the UK regulator, can be a distinct advantage on the international playing field. “We’ve got a great opportunity in the UK to really show what is going to get the investment, which is: Regenerative medicine does work.”

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