A growing number of stem cell companies are seeing the light and shifting their focus to exosome products.
An interesting mixture of companies are lining up to follow Exopharm’s lead and begin human clinical trials of therapeutic exosome candidates.
At least three exosome companies are aiming to start clinical trials during 2020, and several more are close behind. Tracing each company’s development to this point, several striking commonalities can be found.
Some of these companies are pivoting into exosome product development after previously focussing on stem cell research – seeking to harness the inherent therapeutic effects of naïve (naturally produced) exosomes derived from stem cells.
Another main group of companies developing exosomes have entered the area from a quite different start point. These companies and their founders had no particular significant history with stem cells. Instead, they have been founded by parties with a background or an interest in the delivery of biological therapeutics, including genetic material and proteins. Rather than use exosomes in their naïve form, these companies focus on engineering exosomes to deliver a therapeutic payload such as a protein or gene therapy agent to a target cell type.
Exopharm has a hybrid origin and ambitions – founded by a person from the stem cell industry but progressing both naïve exosomes and engineered exosomes.
Despite their different backgrounds, the companies are united by their recognition that exosomes appear to be a new technology offering safe, practical, versatile, and effective options for treating human ill-health in many guises.
The Stem Cell pivot
The downsides of stem cell therapies have driven a set of companies across into exosome research.
One such company is Los Angeles based Capricor Therapeutics. Founded in 2005, the company has been pursuing a cell (cardiosphere-derived cells (CDCs)) therapy treatment of a rare genetic disorder called Duchenne muscular dystrophy.1
But in 2018, the company published data showing that, in Duchenne, the therapeutic effect of CDCs is essentially due to the exosomes that the cells release.2 These exosomes are taken up by heart and muscle cells, with multiple beneficial effects.
Capricor is now investigating CDC exosomes – a product it has designated CAP-2003 – as a ‘next generation’ regenerative medicine for Duchenne, and other diseases of inflammation and fibrosis.3 The company is on track to start clinical trials of CAP-2003 in the first half of 2020, company CEO Linda Marbán recently told Nature Biotechnology.4
Based in Athens, Georgia, US, Aruna Biomedical has an even longer history with stem cells. Started in 2003, Aruna specialises in producing human neural stem cells for sale to researchers. But in 2017 Aruna announced that it would start pursuing the exosomes released by these stem cells as a potential treatment for stroke.5 In animals, the exosomes can cross the blood-brain barrier, reduce inflammation, enhance neural function, and improve motor function and behavioural outcomes, the team has shown.
In October 2019, Aruna received National Institutes of Health funding to support research and development leading up to an Investigational New Drug (IND) application – a key step toward starting human clinical trials – in 2021.6
In contrast, Aegle Therapeutics founded in 2013, has focussed on exosomes right from the start. But company founder Evangelos Badiavas, from the University of Miami, had spent many years researching clinical applications of mesenchymal stem cells (MSCs) and conducting clinical trials on burns and wounds. However, the team grew frustrated with stem cells.
“Given that MSCs are hard to predict and control in vivo, compounded by the high costs of production, our scientists set out to discover ways to harness the healing power of stem cells without using the cells,” Aegle’s website states.7 As MSC-derived exosomes seemed to responsible for MSC’s skin-healing effects, the company is developing candidate exosomes therapies for skin conditions including burns, scarring and epidermolysis bullosa.8 It aims to start clinical trials in 2020.4
Exopharm – which has entered human clinical trials of its wound-healing candidate exosome product called PlexarisTM – also has origins in the stem cell field.9 Company founder Ian Dixon co-founded stem cell company Cynata Inc. in 2011 with the Cymerus stem cell product derived from induced pluripotent stem cells. However, by 2013 is was becoming clear that exosomes delivered most if not all the potential therapeutic benefits of stem cells without all the downsides of therapy with live cells. Dixon founded Exopharm in late 2013 as a cell-free exosome company.
All cells release exosomes, containing a particular cargo of proteins, lipids and ribonucleic acids (RNA) that reflect the nature and status of the cell releasing them.
As a potential therapy, stem cell-derived exosomes have many potential benefits compared to the live cells themselves. Exosomes are considered inherently safer than a therapeutic based in dosing patients with live cells that might behave in unexpected or unwanted ways inside the body. Exosomes are much smaller than cells and can circulate far more freely in the body to reach target sites. The cost and complexity of producing, storing, transporting and administering a live cell therapy would also be much higher, compared to exosomes.
Another exosome-first company gearing up to commence its first clinical trials in early 2020 – Cambridge, Massachusetts-based Codiak – moved into exosomes as a way to deliver biologic cargoes to target cells.
Codiak’s engineered anticancer exosomes are based partly on the research of Raghu Kalluri from MD Anderson Cancer Center at the University of Texas. Kalluri’s work had shown exosomes can act as a potent and safe delivery system for multiple therapeutic payloads, the company reported on its launch.10
In the UK, Oxford-based Evox moved into exosomes as a way to improve gene therapy. Company founder-director Matthew Wood is a University of Oxford academic researching gene therapy for degenerative disorders.11 A key hurdle in the gene therapy field has long been getting gene therapy agents delivered into target cells. In a Nature Biotechnology paper published in 2011, Wood showed exosomes were well suited to the task.12
As exosomes have evolved with the very purpose of travelling the body to deliver a natural payload of proteins and RNA to target cells, they appear ideal for the task of targeted therapeutic delivery of specific nucleic acid sequences.
Each of these companies seek to exploit the same fundamental properties of exosomes as a new treatment technology: excellent biocompatibility, delivery efficiency, safety and logistic benefits.
Like any emerging technology field, there is nothing static about the companies seeking to establish themselves in the exosome space. Several companies which moved from a focus on stem cells to progress naïve exosomes – including Aruna Bio and Capricor – are also now eyeing the opportunity to develop their exosomes as drug delivery vehicles.13, 14
As more exosome clinical trials get underway during 2020, and sector leaders such Exopharm start to report their first clinical trial results, the exosome field is one to closely watch. Positive results are sure to drive more stem cell companies into exosome programs.
Established multinational healthcare companies are also starting to see exosomes as a new modality for advanced medicines across a range of medical areas including regenerative medicine.
2. Aminzadeh, M. A., et al. Exosome-Mediated Benefits of Cell Therapy in Mouse and Human Models of Duchenne Muscular Dystrophy. Stem Cell Reports 10, 942-955 (2018) https://doi.org/10.1016/j.stemcr.2018.01.023
4. Zipkin, M. Exosome redux. Nature Biotechnology 37, 1395–1400 (2019) https://doi.org/10.1038/s41587-019-0326-5
8. Shabbir, A., et al. Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro. Stem Cells and Development 24 (2015) https://doi.org/10.1089/scd.2014.0316
12. Alvarez-Erviti, L., et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology volume 29, pages341–345 (2011) https://doi.org/10.1038/nbt.1807