Long COVID-19 Syndrome is seen in around 10–20% of people previously infected with SARS-CoV2. The wide range of symptoms associated with this condition may be partly due to damage to the tissues and blood vessels of the nervous system. Professor Philip W Askenase, Yale School of Medicine, USA, reviews the evidence to suggest a novel therapy for Long COVID Syndrome, which uses nano packages of molecules, called exosomes, that are administered via the nose to encourage healing and recovery particularly of the neuro-psychiatric aspects of Long COVID. Using exosomes derived from mesenchymal stromal cells and administered nasally may allow researchers to directly target affected cells within the nervous system.
COVID-19 is an infectious disease caused by the SARS-CoV2 virus. People infected with SARS-CoV2 may experience a variety of symptoms, ranging from no symptoms at all, to severe illness requiring hospitalisation. As well as the wide range of symptoms, recovery rates of patients with COVID-19 also vary. Some people will feel better within days to weeks, and most will make a full recovery within 12 weeks. However, around 10–20% of people infected can experience post-acute COVID symptoms beginning with a time gap after cessation of infection. These new onset clinical processes are referred to as ‘Long COVID Syndromes’ (LCS).
Common symptoms associated with LCS include extreme fatigue, shortness of breath, brain fog, and cognitive disorders, as well as changes in smell or taste, and gastrointestinal symptoms. In severe cases of LCS, individuals may even experience a variety of neuro paranoia, or psychosis, rarely leading to suicide. Such symptoms can interfere with daily living and have a negative impact on quality of life. Therefore, understanding more about the mechanisms by which Long COVID is caused may open the door for new therapies to help combat LCS that are the focus of the studies proposed here. In addition, since many of the long-term consequences of infection with SARS-CoV2 are not yet known, and LCS can follow mild and even asymptomatic Sars CoV-2 infections, there may be an increase in LCS patients with neurological or psychiatric complications that become evident in the future.
Professor Philip W Askenase at Yale School of Medicine, USA, explains that the central nervous system (CNS) plays a key role in this delayed development of LCS. Magnetic resonance imaging of brains of individuals who had recovered from COVID-19 three months previously showed damage to the neural vasculature and neural tissues, compared to controls.
While there has been some suggestion that perhaps the virus was able to directly infect tissues of the CNS, it has not been possible to isolate viral particles from cerebrospinal fluid or brain tissues of patients with COVID-19. Cerebrospinal fluid found within the spinal column offers an easily accessible way to sample compounds circulating between the brain, spinal cord and the rest of the body, and has confirmed non-infectious influences of the virus but no direct infection. Instead, inflammation has been observed within these tissues of the CNS. This suggests that it is damaged neural tissues and surrounding blood vessels caused by local immune responses that results in neuro-psychiatric symptoms of LCS, rather than the virus itself. It is important to note that many of these studies sampled tissue from patients who had died from COVID-19, and therefore may have had other health conditions making them more vulnerable to severe COVID-19 illnesses that may not be directly representative of all patients infected with SARS-CoV2, especially those with consequent LCS.
Similarities have been observed between the clinical manifestations of LCS and other conditions that can arise following viral infection, such as myalgic encephalomyelitis, also known as chronic fatigue syndrome. However, Askenase points out that there are some key differences that distinguish LCS from other conditions, including the characteristic alterations of smell and/or taste. He suggests that the pathogenesis of LCS is likely to be multifactorial, consisting of ongoing immune responses to residual SARS-CoV2 infection or to viral proteins that remain in the body after infection is resolved. Previous work has shown that attempting recovery via high-intensity exercise can accentuate the dominant vascular pathology and further promote profound fatigue, confirming the crucial contribution of vascular dysfunction to LCS.
Nano-sized sacks called extracellular vesicle exosomes
Askenase is particularly interested in the involvement of the tiny blood vessels in the nervous system, also called the CNS microvasculature. He has recently reviewed whether tiny sack-like packages of membrane-protected molecules, called exosomes, may offer an attractive natural biological therapy for treatment of LCS. These recently appreciated nano-sized packages made by all cells contain different proteins like enzymes, but uniquely can also contain genetic material such as a variety of RNAs and perhaps DNA as well. These genetic molecules can be transferred by the exosomes to other cells, sometimes causing changes in expression of their DNA-composed genes and thus activities of the cells.
In particular, Askenase’s work focuses on exosomes derived from mesenchymal stromal cells (MSC) found in various connective tissues in rare quantities. These potential healing and trophic cells (that promote growth and maturation) are commonly found in adult bone marrow, are also present in umbilical cord tissues and placental amnion that encloses the embryo, adhere to plastic flasks, and are self replenishing − enabling expansion from small numbers of cells to 100%. Very importantly, a variety of prior studies have shown that MSC and especially their derived exosomes may have a trophic-positive role in healing within the body; with anti-inflammatory, anti-immunological, and anti-cell death effects, as well as the ability to promote growth and function of local vasculature. These beneficial healing effects of modest numbers of these MSC-derived exosomes have been demonstrated in a range of experimental animal models of clinical diseases such as stroke and myocardial infarction, as well as acute failure and ischemic injury of kidney, liver, and CNS. This includes previous work done by the Askenase research group in immune suppression of T-cell mediated tissue inflammation and neural and neural vasculature damage of spinal cord injury.
Since vessel damage in the CNS microvasculature and effects of inflammation represent prominent injuries in LCS, repairing the micro vasculature capillary cells that make up the small blood vessels may help prevent or treat LCS, and this is where therapy with MSC-derived exosomes may come into play.
Askenase emphasises that it may be possible to harness the healing, anti-inflammatory and anti-immunological properties of MSC-derived exosomes for therapy to specifically target macrophages among the infiltrating immune-system cells and local cells in the CNS such as related microglia, that are then stimulated to further release their secondary healing exosomes to help repair neighbouring capillary cells of the neural blood vessels and thereby restore normal microvasculature.
He proposes that the ability to grow, greatly enrich, and harvest these MSC-derived exosomes offers a potential therapeutic treatment for the neurological and vascular effects of LCS. Several studies have already demonstrated the benefits of MSC and MSC-derived exosome therapy in the severe pneumonia of active COVID-19 infections. One example of this is a study in which MSC-derived exosomes administered via intravenous injection to patients with active COVID-19 infections caused a reported reduction in inflammatory markers and decreased numbers of inflammatory white blood cells, with clearing of pneumonia. Although there was no control group with which to compare these findings, the results show that the therapy was well tolerated and safe. Indeed, there are already a number of other registered clinical trials that aim to further explore the use of MSC-derived exosomes for treating COVID-19 related acute infectious diseases.
Exosomes naturally cross the blood–brain barrier
One challenge that the researchers need to overcome is the way in which the exosomes would be given to patients. The blood–brain barrier presents a highly selective boundary around the vulnerable brain tissue that protects it from harmful compounds. The cells that make up this barrier filter the blood supply entering the brain, removing toxins and allowing nutrients to pass through, while also taking waste products away from the brain tissue.
Administering MSC-exosome therapy via the nose, where they pass through the tiny spaces between the descending olfactory (smell) nerves and the skull of the cribriform plate, should allow these extracellular vesicles to move into the brain. This is a method already used in previous studies, that showed successful nasal administration of exosomes for other inflammatory conditions, such as multiple sclerosis, Alzheimer’s and Parkinson’s disease. Coupled with existing evidence that shows how MSC-derived exosomes can be used against acute COVID-19 infections, and in a variety of systemic inflammatory disease models and neuropathology models of Alzheimer’s and Parkinsons disease in animals, it is postulated that it may also be possible to harness this approach for nasal administration of MSC-exosomes for treatment of the neuro psychiatric aspects of LCS.
Progressing the field of immunology
Askenase has made valuable contributions to the field of immunology. He has discovered novel roles of B-cells (antibody producing cells), and other white blood cells (mast cells and basophils) in T-cell immune responses and is making exciting discoveries about the links between gene-influencing miRNA in exosomes, and immune regulation. As part of this work, he aims to identify therapeutic exosomes useful for patients with certain conditions to achieve safer and more physiological targeted immunotherapy treatments. Recently, Askenase has focused on COVID-19, and Long COVID in particular. He proposes that neuro-psychiatric dominated cases of LCS are frequently caused by damage to vessels and tissues of the nervous system, and it may be possible to directly target these areas of injury by administrating natural biological healing exosomes through the nose. Using in particular exosomes derived from trophic mesenchymal stromal cells may allow research physicians to directly target affected cells within the nervous system, uniquely stimulating them further to release their exosome nano packages of molecules that can help restore vascular function for patients with these forms of LCS. If successful, this form of therapy might improve LCS patient health and quality of life, as well as reducing the physical, emotional, and financial costs of managing this common consequence of COVID-19 disease. For details see www.frontiersin.org/articles/10.3389/fnano.2022.987117/abstract
- Askenase, PW, (2022) Recommendation: Treatment of clinical Long COVID encephalopathies with nasal administered mesenchymal stromal cell extracellular vesicles. Frontiers in Nanotechnology, In press. www.frontiersin.org/articles/10.3389/fnano.2022.987117/abstract
- Askenase, PW, (2021) Ancient evolutionary origin and properties of universally produced natural exosomes contribute to their therapeutic superiority compared to artificial manoparticles, Int J Mol Sci, 22(3), 1429, 1–28. doi:10.3390/ijms22031429.
- Askenase, PW, (2021) Exosomes provide unappreciated carrier effects that assist transfers of their miRNA to targeted cells; they are ‘the elephant in the room’, RNA Biology, 18(11), 2038–53. doi:10.1080/15476286.2021.1885189.
- Nazimek, K, et al, (2021) Antibodies enhance the suppressive activity of extracellular vesicles in mouse delayed-type hypersensitivity, Pharmaceuticals, 14(8), 734, 1–25. doi:10.3390/ph14080734.
- Askenase, PW, (2020) COVID-19 therapy with mesenchymal stromal cells (MSC) and convalescent plasma must consider exosome involvement: Do the exosomes in convalescent plasma antagonize the weak immune antibodies? J Extracell Vesicles, 10(1), e12004, 1–19. doi:10.1002/jev2.12004.
- Katarzyna, N, (2020) Approaches to inducing antigen-specific immune tolerance in allergy and autoimmunity: Focus on antigen-presenting cells and extracellular vesicles, Scand J Immunol, 91(6), e12881, 1–19. doi:10.1111/sji.12881.
- Nazimek, K, et al, (2020) Orally administered exosomes suppress mouse delayed-type hypersensitivity by delivering miRNA-150 to antigen-primed macrophage APC targeted by exosome-surface anti-peptide antibody light chains. Int J Mol Sci, 21(15), 5540, 1–33. doi:10.3390/ijms21155540.
- Włodzimierz, P, et al, (2015) From mysterious supernatant entity to miRNA-150 in antigen-specific exosomes: a history of hapten-specific T suppressor factor. Arch Immunol Ther Exp (Warsz), 63(5), 345–56. doi:10.1007/s00005-015-0331-4.
Professor Askenase’s research focuses on allergy, asthma, immunology, and infectious diseases.
Katarzyna Nazimek and Krzysztof, Bryniarski, Kracow, Poland
Philip Askenase completed his MD at Yale University in 1965. He is a professor at Yale School of Medicine where he has made many accomplishments in the fields of allergy and immunology. His current work involves a new regulatory suppressor T-cell mechanism involving production of antigen-specific suppressor exosomes, coated with an activated exosome subpopulation.
Yale School of Medicine
Section of Rheumatology, Allergy & Clinical Immunology
200 Leeder Hill Drive, Apt 2402
Hamden, CT 06517, USA