Exosomes show potential to treat myriad conditions, including cancer and inflammation, but experts are divided on whether the therapies are ready for the limelight.
Pictured: a conceptual drawing of the small extracellular vesicles, including exosomes/iStock, KS Kim
Imagine a future where, instead of drugs that carry the risk of allergic responses and adverse events, materials made naturally by the human body can be used as medicine. A novel modality, exosomes might be on the cusp of making that future a reality, experts told BioSpace.
Exosomes are membrane-bound sacs measuring tens of nanometers in diameter. They are produced by cells and may contain molecules such as RNA and enzymes to communicate with other cells. Since the 2010s, scientists have known that exosomes also have the potential to treat many conditions, particularly inflammatory ones.
Over the past five years, investors have poured hundreds of millions of dollars into exosome-based therapeutics. Since 2018, the database clinicaltrials.gov has logged more than 100 trials involving exosomes, many of which are assessing therapeutics tailored to specific conditions like cancer.
This boom has been fueled by incremental advances in research and a growing discontent with traditional cell therapies, which can be invasive, expensive and immunogenic, said Steven Stice, co-founder and CSO at Aruna Bio, which recently won FDA approval to begin clinical trials of its exosome, AB126. Exosomes appear to be compatible with the body and unlikely to be treated by the immune system as a foreign particle, potentially making them a safer alternative to cell therapy. But not everyone agrees.
Are Exosomes Ready for the Clinic?
Experts are divided on whether or not exosomes are ready to be used as therapeutics.
Theresa Whiteside, a professor of immunology at the University of Pittsburgh who studies the use of exosomes as tumor biomarkers, does not believe exosome-based therapeutics are ready for clinical study. “We have no idea what regulates [exosome biology],” Whiteside told BioSpace. “At the moment, it’s a confusing picture.”
In the other camp, Sharanjot Saini, an associate professor in the department of biochemistry and molecular biology at Augusta University, is using exosomes to deliver drugs for neuroendocrine prostate cancer. Exosomes engineered by Saini’s lab to specifically deliver two drugs to the prostate “significantly” reduced tumor growth in mouse studies. Saini told BioSpace that if initial safety and toxicity tests are conducted with rigor, there is nothing standing in the way of using exosomes as therapeutics.
Despite her objection to moving too quickly on the idea of exosome-based therapeutics, Whiteside does support their use as biomarkers. Studies from her lab show clear differences in the exosomes derived from healthy people and those from patients with tumors, and even in the exosomes from different types of cancer patients. Eventually, describing these exosomes in detail could help inform patients’ response to immunotherapy, Whiteside said.
Key Players in the Exosome Space
Several biopharma companies are working to develop exosome-based therapeutics for a wide array of conditions. The exosome diagnostics and therapeutics market is projected to grow by some $419 million during the five-year period ending in 2026, with North America accounting for 40% of that growth, according to a report published by Technavio.
Aruna’s AB126 is the first exosome to enter human trials for a neurological indication. The company claims it can cross the blood-brain barrier and could help ischemic stroke patients by reducing inflammation in the brain, according to a press release, which notes plans to expand the asset into other neurological indications, including amyotrophic lateral sclerosis (ALS).
Meanwhile, Rochester, Minnesota–headquartered RION in January began a Phase IIA trial for its purified exosome product, which is derived from platelets, for the management of diabetic foot ulcers. And in July 2023, Texas–based Direct Biologics announced promising results from a Phase II trial showing that its exosome, ExoFlo, reduced mortality in long COVID patients with acute respiratory distress syndrome.
In parallel with the development of new therapies, firms are considering their manufacturing needs. In 2021, healthcare manufacturing giant Lonza acquired the exosome manufacturing facility of the now-defunct Codiak BioSciences. And contract development and manufacturing organizations (CDMOs) like RoosterBio have ramped up their services and partnered with other companies to address bottlenecks in exosome manufacturing. The trend is also taking off in Europe, where exosome-based therapeutics developer EXO Biologics launched a CDMO called ExoXpert to market their proprietary platforms as a service to other companies.
Regulating Exosomes
Because exosome-based therapeutics are so new, the FDA and other regulatory bodies such as the European Medical Agency (EMA) are working to draft relevant guidelines for their use. Eric Leire, CEO of Genflow Biosciences, which is using ExoXpert’s services to make mRNA-bearing exosomes, likened the current process to flying a plane and building it at the same time.
CDMOs currently comply with current good manufacturing practices (cGMP), but the FDA has partnered with academic researchers to scrutinize the process and set quality control standards. Organizations like the International Society for Extracellular Vesicles (ISEV) are also filling this gap by periodically releasing recommendations for working with exosomes, the latest of which were published in 2023. These new guidelines not only outline best practices for isolation and purification but also clearly specify what can and cannot be called an exosome.
When it comes to clinical trials, exosomes straddle two key regulatory areas: biologicals and cellular and gene therapy products (called advanced therapy medicinal products by the EMA). Walking that line and ensuring that any exosome-based products meet the safety and quality criteria in both fields is a stumbling block, EXO Biologics Chief Business Officer Romain de Rauville told BioSpace. He added that harmonization across different regulatory bodies should be made a priority to ensure exosome manufacturing and testing can be done smoothly across global sites.
Tracey Worthington-Stice, co-founder and chief operating officer at Aruna Bio, stressed the importance of working closely with the FDA and beginning the process early. Doing so gave Aruna “a leg up,” she told BioSpace. The team also filed the Investigational New Drug Application and other regulatory forms themselves, which Stice noted gave them a clear understanding of the process.
Manufacturing Exosomes at Scale
Aruna Bio makes its exosomes in an in-house cGMP facility, which was “designed for flexibility,” Stice said. The adaptable nature of the facility allows the team to keep a close eye on the process and tweak the protocols when needed, which Stice said was critical for ramping up production and getting AB126 into clinic trials.
Not all companies can afford in-house cGMP manufacturing, however. Finding people with the right expertise is also vital, Stice said. This is where CDMOs like ExoXpert come in. When Genflow decided to pivot from an AAV-based gene therapy to exosomes, it partnered with ExoXpert to make mRNA- and cDNA-containing exosomes. ExoXpert’s team offered crucial manufacturing know-how that Genflow lacked, Leire said, helping the latter push through what would have been an expensive and prolonged affair.
Particularly challenging has been matching the scales of the upstream process, including getting cells to make the right kind of exosome, with the scales of the downstream process, like purifying the exosomes and getting consistent batches, de Rauville said. But Saini noted that academic developments and concerted efforts by ISEV to streamline and standardize a previously disjointed field have made these processes easier. “I have seen that shift from 2015. I think now . . . there is a good idea of what to expect with each exosome isolation method.”
Going forward, the objective will be to back up the promise of exosomes with meticulous trials, de Rauville said. For Stice, there is value in taking therapeutics forward despite existing knowledge gaps. “There’s so many unmet needs and diseases such as stroke and ALS,” he noted. “We need solutions now.”
Sruthi S. Balakrishnan is a freelance academic editor, science writer and fact-checker based in Santa Barbara, California. She can be reached at sruthisb@sciscriber.com.
