Developing iPSC-derived MSC-based therapies: an interview with Ross Macdonald, Cynata Therapeutics

In this interview from the World Stem Cell Summit (22–26 January, Miami, FL, USA), Ross Macdonald discusses the advantages of MSC-based cell therapies.

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Mar 05, 2018
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What is Cynata Therapeutics Ltd?

Cynata Therapeutics Ltd (ASX: CYP) is a relatively young stem cell and regenerative medicine company. We were formed in 2013 in Australia based on a novel technology platform, Cymerus™, from the home of stem cells, the University of Wisconsin-Madison (WI, USA). The inventors of Cymerus are industry luminaries, and include James Thomson, Ph.D., who described the first embryonic stem cell.

What are the advantages of using induced pluripotent stem cells (iPSCs) to generate mesenchymal stem cells (MSCs)?

Cynata’s Cymerus technology platform is a new approach to manufacturing MSCs. Rather than deriving MSCs from primary tissue sources, such as bone marrow or adipose tissue, our MSCs are manufactured from iPSCs. It is now very clear that MSCs have a limited capacity for self-renewal, and are fairly scarce in tissues. MSCs are not present in the numbers required for clinical trials, let alone for commercial application, so they have to be expanded.

As an adult stem cell, MSCs can only multiply a limited number of times before they start to demonstrate senescence properties that reduce their clinical utility, though they may still be alive and viable. This severely hampers the ability to manufacture commercial quantities of consistent, safe and effective therapeutic MSCs.

This limitation has come to light in several approaches. First of all, early clinical studies of MSCs involved small numbers of cells manufactured for a small numbers of patients. The results were promising, but when the number of patients was expanded to accommodate larger clinical studies, more MSCs were required and the results weren’t consistent with earlier data. Although many organizations are working on technologies to allow for the increased expansion of MSCs, it’s important that we see the data.

A different approach to stem cell therapies has been enabled through the development of iPSCs. Embryonic stem cells still face many challenges from an ethical point of view, but iPSCs avoid all of those controversies and the progress that researchers have made in iPSC derivation is substantial. iPSC manufacture is now more consistent, reproducible and they essentially serve as an infinitely expandable starting material that can be differentiated into any cell, which, in Cynata’s case, is MSCs.

How does Cynata’s Cymerus platform work?

Cymerus is a patented stem cell manufacturing process that avoids the problems often associated with deriving MSCs and primary tissue sources, and has the potential to generate large-scale, low-cost MSCs based on a single blood donation from one adult donor. Cymerus uses iPSCs taken from one banked blood donation to generate mesenchymoangioblasts, a precursor that produces an unlimited number of consistent MSCs. All of the expansion is done at the level of the iPSC, which we know can expand 10–72 times without change, then differentiated into a very robust MSC.

Read more: Limitless starting materials for large-scale manufacture of MSCs – what does the future hold?

Cynata obtained the original seed stock from Cellular Dynamics International, Inc. (WI, USA), which was acquired by FUJIFILM (Japan) in 2015. Cellular Dynamics was the first company to have GMP-grade iPSCs. We manufacture our finished product through Waisman Biomanufacturing (WI, USA), a GMP-compliant contract manufacturer, without using any xenobiotic products. This process ensures there are no undifferentiated cells or other impurities in the finished product.

What are the advantages of an off-the-shelf stem cell therapy?

An off-the-shelf, universal product doesn’t require human leukocyte antigen (HLA) matching of the donor and recipient. With iPSC-derived MSCs, a true off-the-shelf product is feasible, and that's our goal. In 2016, we secured approval from the Medicines and Healthcare products Regulatory Agency (UK) to start a clinical trial, after industry scepticism that iPSC-derived products would be a challenge with regulators around the world.

Approval for our trial demonstrated that regulatory agencies are amenable to this type of therapy, and enabled us to start a trial in 2017 for our lead therapy, CYP-001, in the indication of graft vs. host disease, which marks the world’s first clinical trial of allogenic iPSC-derived MSCs.

There’s an important distinction to make between clinical research and a clinical trial. For example, Dr Masayo Takahashi’s macular degeneration study at the RIKEN Centre for Developmental Biology (Japan) is research, whereas our study is the first clinical trial of its kind.

Can you give us an update on this trial?

We recently completed a Data and Safety Monitoring Board analysis, which marked the halfway point of the trial. The analysis identified no safety concerns and also, coincidentally, showed the cells appeared to work very effectively in that all patients responded to treatment. The trial should complete around the middle of 2018.

The first serious adverse effect was recently reported in the Takahashi macular degeneration trial. Could this affect Cynata’s trial?

Dr Takahashi said the serious adverse event won't affect her research and it likely won't affect our trial either, as our studies are very different. Having said that, safety is a primary concern. We were pleased to report in January 2018 that no treatment-related serious adverse events or safety concerns have been identified in our Phase I trial to date.

What do you see as trends for 2018?

It's all about results. If the companies working in this sector generate positive data, whatever their product, that drives the industry. We’ve seen this time and time again in drug development; there are waves of enthusiasm and despair, until you have a breakthrough or you have nothing. For example, at one point many people thought monoclonal antibodies were interesting but that they’d never make it as mainstream therapeutics. Now there are monoclonal antibodies in the top 10 drugs worldwide. 

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