A conversation with Dr. Michael Chopp, PhD, Vice Chairman, Department of Neurology, Scientific Director, Neurosciences Institute, Zoltan J. Kovacs Chair in Neuroscience Research at Henry Ford Hospital, and Distinguished Professor of Physics, Oakland University, about the novel use of exosomes and miRNA as possible therapeutic agents in stroke patients.
Interviewed by Alexis N. Simpkins, MD, PhD, Assistant Professor of Neurology, University of Florida School of Medicine.
They will be discussing the paper “Exosome Therapy for Stroke,” published in the May 2018 issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.
Dr. Simpkins: Exosomes appear to be a promising new therapeutic target for stroke given their ability to potentially help with neuroplasticity and vascular remodeling. Changes in the blood induced by acute stroke can be rapid. How quickly does the concentration and content of exosomes change? Do you foresee exosome therapy being best used in the acute treatment of stroke or in subacute phase during stroke recovery?
Dr. Chopp: Exosomes are exceptionally potent mediators of biological function. Exogenously administered exosomes interact with parenchymal and endothelial cells. They contain protein. RNA, and lipid cargo that are highly efficiently delivered to receptive cells. The exosomes also may contain molecular machinery to facilitate and amplify biological function of the delivered cargo. Particularly important is the microRNA (miR) content of the exosomes. miRs are master switches, and each miR can potentially impact and modulate the translation of hundreds of genes. The nanometer dimension of exosomes and their cell surface receptors facilitate their entry into the brain and their ability to permeate the central nervous system. In addition, absorbed exosomes induce a sequential chain reaction release of exosomes from target cells that further amplifies their biological function. Thus, although the numbers of administered exosomes are clearly diluted after intravascular administration, exosomal content, and specifically their miR content, as well as subsequent releases of secondary exosomes, greatly amplify exosome function. I do foresee the use of exosomes in both the treatment of acute stroke, as well as in subacute and chronic stroke. Harnessing the potential of exosomes, endogenous mediators of nearly all cell and inter-organ communication, hopefully, will lead to efficacious neurovascular protective and restorative therapies for stroke, neural injury and neurodegenerative diseases. The question should not be whether exosome therapy is best used in the acute or chronic treatment of stroke. What has to be asked is, what are the optimal exosome therapies for acute and for chronic treatment of stroke?
Dr. Simpkins: The recent positive extended time window endovascular trials showed that some patients with large vessel occlusion may be able to maintain circulation to areas that would otherwise infarct through collateral vessels. How might exosome therapy be used to maintain collateral blood flow and affect neurovascular coupling in the acute setting? There are also patients that do not have ideal imaging profiles and even patients that receive endovascular therapy that still have disabling neurologic deficits. How might exosome therapy be used in these different situations?
Dr. Chopp: Secondary thrombosis evoking tissue hypoperfusion and subsequent growth of the infarction frequently occurs post thrombectomy and thrombolysis. Upstream arterial occlusion initiates sets of downstream inflammatory events and release of pro thrombotic and coagulation factors, including neutrophil extracellular traps, that negatively impact the integrity and patency of the microvasculature, and thereby compromise adequate tissue perfusion. Although additional research is warranted, exosomes, by inhibiting neurovascular inflammatory response to stroke, may maintain collateral and downstream tissue perfusion and neurovascular coupling and thereby increase the numbers of eligible patients who will benefit from conventional FDA-approved therapies. For those patients who receive endovascular therapy and yet suffer disabling neurologic deficits, treatment with exosomes by robustly promoting central nervous system plasticity and neurovascular remodeling may result in improved neurological outcome.
Dr. Simpkins: How may the common stroke risk factors modulate the content and presence of exosomes, and what might these differences mean for developing exosome therapy?
Dr. Chopp: Diabetes, hypertension, age all likely affect the therapeutic targets, and therefore the types of exosome-based therapies. Thus, a diabetic patient may benefit from treatment with exosomes derived from a specific parental cellular source, as well as exosomes whose miR content in particular is altered, e.g. enriched, to specifically impact the underlying diabetic vascular diseases. As with stroke in the absence of comorbidities, with stroke in conjunction with comorbidities, such as diabetes, there is multi-organ response, e.g. cardiac, renal, and microbiome, that will impact morbidity and mortality from the ictus. Exosomes play a primary role in mediating organ interactions, and optimized exosomes, as well as specific lineage exosomes, may be needed to address the systemic response to particular conditions of stroke. Bottom line is, risk factors affect how endogenous cells respond to stroke, and also may determine the types of exosomes employed to treat stroke.
Dr. Simpkins: You mention that it will be important to ensure that the exosomes are not oncogenic. Are there other possible potential adverse effects of using exosomes as therapeutics?
Dr. Chopp: Although, to my knowledge, there are no data implicating exosomes derived from healthy cells in stimulating or exacerbating cancers, and without nuclei, clearly exosomes do not proliferate, safety of exosome therapy must be ascertained. It is essential to always know the risk-benefit ratio for all therapeutics. It is not inconceivable that exosomes, given their highly restorative and remodeling effects on vascular and parenchymal cells and tissues, may act to nurture and enhance tumors. However, to date, there is no evidence for exosomes being oncogenic — this, however, does not free us from directly and fully evaluating oncogenic potential of exosome therapy.
Dr. Simpkins: Other organ systems, such as the cardiac system, are often stressed during acute ischemia. Would you envision the tailored treatments to include multi-system targets?
Dr. Chopp: As emphasized above, we cannot be provincial and narrow in our treatment of stroke and neural injury. Therapies are required to ameliorate the often adverse systemic response to stroke, and it is these adverse responses that may greatly impact recovery. The brain talks to the body, to all organs and cells, to a prominent extent via microvesicles released by brain tissue. Even the genes in bone marrow cells in the recesses of the body are directly affected and altered by the brain insult. Clinical and preclinical data strongly support post-stroke brain multi-organ interaction, with the heart — even a pre-stroke normal heart — demonstrating cardiac dysfunction post stroke, with dysfunction exacerbated by comorbidities. Exosomes that carry different cargos of miRNAs that have effects on different organ systems delivered in the acute or subacute period may be efficacious in treating multi-organ adverse response to stroke.
Dr. Simpkins: What are the next steps in translating exosome therapy to stroke patients?
Dr. Chopp: Although there is substantial therapeutic potential of exosome-based treatment of acute and chronic stroke, both ischemic and hemorrhagic stroke, major investments at the preclinical, manufacturing, and safety levels are required. The FDA protocols for an IND for drug, and even more directly, for cell-based therapies should be and will likely be followed. Preclinical studies identifying a specialized form of exosome therapy (parental cell source, tailored e.g. miR content) for a specific clinical stroke target (e.g., cardioembolic, thrombotic, watershed, hemorrhagic) should be performed. This would be followed by additional preclinical studies optimizing route of exosome administration, which may differ with time of exosome administration and therapeutic target, and dose-response and therapeutic window studies must be performed. Once the preclinical efficacy and safety data are obtained, then the production/generation issues (scaling, consistency, reproducibility, GMP production) become paramount prior to initiating clinical trials. We now have an opportunity to develop a transformative biological therapeutic in the form of exosome therapy for stroke. The preclinical data on the therapeutic efficacy of exosome therapy for stroke, brain injury, and neurodegenerative disease, both in the central and peripheral nervous systems, cry out for accelerated development.
Dr. Simpkins: Agreed. Thank you for participating in the Blogging Stroke interview.