Clinical trial led by Thomas Jefferson University Hospital paves the way for innovative topical treatment
PHILADELPHIA – A minimally invasive treatment for individuals suffering from loss of smell and taste could become a reality. Led by Thomas Jefferson University Hospital otolaryngologist Dr. David Rosen, a team of physicians and researchers have developed a first-of-its-kind topical platelet-rich plasma treatment. Preliminary results from an ongoing clinical trial show promise in restoring patients’ sense of smell and taste.
Smell and taste disturbances known as anosmia and parosmia have grown in awareness in recent years since it is a common symptom of COVID-19. While the symptoms typically resolve for most individuals, up to 1.5 million people in the United States continue to experience long-term distortion of the sense of smell and taste.
Platelet-rich plasma (PRP) is a common restorative therapy used to regenerate cells, heal tissue, and address an array of medical conditions from healing injured muscles and tendons to increasing hair growth and reducing the appearance of scars. Animal studies have shown that PRP helps regenerate the olfactory epithelium, which may be the site affected in COVID-19 induced olfactory dysfunction (OD). As smell and taste are closely interrelated, improved sense of smell can help with sense of taste as well. Until now, PRP has been used as a nasal injectable in several small clinical trials for smell loss. Although the results were promising, nasal injections can be uncomfortable and invasive for patients.
“I’ve dedicated over two decades to helping patients recover from the loss of taste and smell,” said Dr. David Rosen, MD, Otolaryngologist, Thomas Jefferson University Hospital. “It was very important to me and our team to explore less invasive options as this issue has become increasingly prevalent due to COVID-19. The results of phase I of the clinical trial have been promising and we are looking forward to phase II to further improve the treatment.”
The new topical PRP treatment consists of monthly applications for a minimum of three months. A recent phase I clinical trial of eight patients who had at least six months of olfactory disturbance has shown preliminary success with 50 percent of participants experiencing clinically significant improvements in smell and taste. While phase I only consisted of eight patients, it is the largest pilot study to date for the use of PRP in treatment of OD and the first study to develop methods for topical delivery in human subjects. The new treatment has also been provided to dozens of additional patients independent of the phase I clinical trial with promising results.
A planned phase II study aims to exclusively look at patients who developed long term olfactory disturbance following recovery from COVID-19 infection. This will help the research team better understand patient variables and the number of treatments required to maintain sustainable improvements in smell and taste.
Majority of the studies focusing on MSC-derived exosomes have demonstrated regenerative potential, immune-modulatory functions, anti-inflammatory effects, similar to their parents, i.e. Mesenchymal stem cells. In preclinical set up, MSC-derived exosomes have demonstrated aptitude as an acellular alternative to cell-based therapy, against Acute Respiratory Distress Syndrome (ARDS). These studies have further confirmed that post-exosomal infusion, the associated cytokine storm and pro-inflammatory signalling biomolecules were considerably reduced that were primarily responsible for ARDS pathogenesis. Further analysis confirmed that the exosomes also increased the level of anti-inflammatory signalling mediators that can reduce the severity of the lung injury through increase permeability and functional aspects of alveolar epithelium, as a result of which, the exchange of oxygen-rich air is easily facilitated.
Further deep diving into the same, the ability of exosomes to transfer mitochondria to alveolar cells further increased their survival rate, and thus, facilitated cellular regeneration. These effects have paved the way towards the therapeutic use of this novel acellular alternative Beyond their effects in preclinical model of acute lung disorders, MSC-derived exosomes were also found to be responsible for direct inhibition of viral multiplication With several studies investigating the bio-distribution of this cellular cargo in preclinical setup, it has been quite evident that these exosomes have the potential to alter a variety of different pathways to facilitate active cellular communication. The intrinsic component of the exosomes, miRNAs, are reportedly found to be the key component that is responsible for many physiological processes, like development, epigenetic alterations, immune regulations, etc. By using near IR dyes, several studies have figured out different techniques to track in-vivo bio-distribution of exosomes upon systemic delivery in different animal models.
Several studies have confirmed their reachability to different organs, like in intra-cerebral haemorrhagic rat models, exosomes could reach to the brain upon the intravenous administration. Intravenous administration of exosomes in a mouse model with acute kidney injury shows their accumulation in the kidneys, further confirming exosomes strong paracrine pathways for instant reachability to the site of injury.
Multiple studies have demonstrated that miRNAs secreted by exosomes are very crucial for accelerated lung recovery, particularly in patients suffering from viral infections like influenza, hypoxia-induced pulmonary hypertension, ventricular induced lung injury, etc. Wang et al. observed and studied active regulation of miRNAs during early and late-stage repair of lung damage in the mouse model. This study further indicated that certain miRNAs like miR-290, miR-21, let-7 and miR-200 played a major role in lung regeneration, immune-regulation, and immune-modulation. Alipoor et al. presented strong experimental evidence that stem cell-derived exosomes can deactivate the signalling pathways associated with hypoxia that can also facilitate reduced hypertension and inflammation, specifically evident in the respiratory disorders. Beyond their effects in a preclinical model of acute lung disorders, MSC-derived exosomes are also found to be responsible for direct inhibition of viral multiplication. Studies have confirmed that MSC-derived exosomes secrete miRNA, which acts as a silencing complex and further alters the expression of the cellular receptors through epigenetic changes that help in blocking the entry of many RNA viruses like influenza, hepatitis C and also Coronavirus. In a pig model of influenza, intra-tracheal administration of MSC-derived exosomes, 12hrs post-infection, significantly reduced virus shredding.
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