revolutionary Cell Therapy – based technology, loaded with CBD

 

CBD DELIVERY BY EXOSOMES PATENT APPLICATION FILED APRIL 6, 2020

 

Background

The world is suffering from a rapid rise in illness due to the fast growing spread of the COVID-19 pandemic. The lungs are the organ most affected by COVID-19, causing pneumonia that rapidly progresses to acute respiratory distress syndrome and can further result in respiratory failure, septic shock, multi-organ failure, and in the most severe cases, death.

Exosomes have emerged as promising nanocarriers for drug delivery and targeted therapy. Exosomes are natural membrane vesicles of endosomal origin, secreted by various cells including mesenchymal stem cells (MSCs). Exosomes carry proteins, lipids, and genetic materials reflective of their cell origins, which facilitate intercellular communication and induce a multitude of biological effects, locally or distally, such as repairing tissue damage, suppressing inflammatory responses and modulating the immune system.  Exosomes are easily traceable and target specific areas.

Recent studies have demonstrated that exosomes derived from MSCs can promote regeneration and improve immune reaction processes in damaged tissues. Exosomes contain anti-inflammatory agents that are able to target inflamed organs.

The Coronavirus (Covid 19)

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in December 2019 in Wuhan, the capital of China’s Hubei province, and has since spread globally, resulting in the ongoing 2019–20 coronavirus pandemic. The first confirmed case of what was then an unknown coronavirus was traced back to November 2019 in Hubei province.

As of April 23, 2020, more than 2.65 million cases have been reported across 185 countries and territories[1], resulting in more than 185,000 deaths. More than 723,000 people have recovered[2].

The virus is primarily spread between people during close contact, often via small droplets produced by coughing, sneezing, or talking. After breathing out produces these droplets, they usually fall to the ground or on to surfaces rather than remain in the air over long distances. People may also become infected by touching a contaminated surface and then touching their eyes, nose, or mouth. The virus can survive on surfaces for up to 72 hours. It is most contagious during the first three days after the onset of symptoms, although spread may be possible before symptoms appear and in later stages of the disease.

The World Health Organization (WHO) declared the 2019–20 coronavirus outbreak a Public Health Emergency of International Concern (PHEIC) on 30 January 2020 and a pandemic on 11 March 2020. Local transmission of the disease has occurred in most countries across all six WHO regions.

The lungs are the organs most affected by COVID‑19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs.  COVID-19 causes pneumonia that rapidly progresses to acute respiratory distress syndrome (ARDS) which further results in inflammation, respiratory failure, septic shock, and/or multi-organ failure.

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastricduodenal and rectal epithelium.  ACE2 is present in the brain, and there is growing evidence of neurological manifestations in people with COVID‑19. It is not certain if the virus can directly infect the brain by crossing the barriers that separate the circulation of the brain and the general circulation. Common neurological presentations include a loss of smell, headaches, nausea, and vomiting. Encephalopathy has been noted to occur in some patients (and confirmed with imaging), with some reports of detection of the virus after cerebrospinal fluid assays although the presence of oligoclonal bands seems to be a common denominator in these patients[3].

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease[4]. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function[5]. A high incidence of thrombosis (31%) and venous thromboembolism (25%) have been found in ICU patients with COVID‑19 infections and may be related to poor prognosis. Blood vessel dysfunction and clot formation are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in patients infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside with the presentation of viral pneumonia[6].

As of April 2020, there is no specific treatment for COVID‑19.[6][128] Research is, however, ongoing. There are multiple attempts in progress to develop a vaccine. In late February 2020, the World Health Organization (WHO) said it did not expect a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus, to become available in less than 18 months[7].

Research into potential treatments started in January 2020 and several antiviral drugs are in clinical trials[8]. It seems that cell therapy may play a role in treating the COVID-19 infection and body immune system reaction. Several clinical studies are conducted using different Stem Cells treatments and Exosomes[9].

All new treatments and drugs under development will need to go through clinical studies to demonstrate safety and effectiveness for the disease.

There is growing concern, including by the director of the CDC, that a second wave of coronavirus will emerge in the fall and that its effects are likely to be even more devastating than the first wave[10],[11].

Exosomes

Mesenchymal stem cells (MSC) are reported to show therapeutic effects in inflammation and injury. Hundreds of clinical studies are using these cells and several endowments have already been approved for use by the Food and Drug Administration in the US (FDA). In the recent years, studies have reported that MSC-derived nano patrticals, named “exosomes”, have functions similar to those of MSCs, such as repairing tissue damage, suppressing inflammatory responses and modulating the immune system.

Exosomes are endosome-derived small membrane vesicles, approximately 30 to 100 nm in diameter, and are released into extracellular fluids by cells in all living systems. They are generated by many cell types and contain proteins and lipids but also mRNAs and microRNAs (miRNAs)[12]. Exosomes are well suited for small functional molecule delivery. Increasing evidence indicates that exosomes have a pivotal role in cell-to-cell communication[13]. In contrast to transplanted exogenous MSCs, the MSC-derived exosomes do not proliferate, are less immunogenic, and are easier to store and deliver than MSCs.

Recently, it has been shown that the secretion of different factors through exosomes, orchestrate the principle mechanisms of action of MSCs after infusion. The use of MSC-derived exosomes may provide considerable advantages over their counterpart live cells, potentially reducing undesirable side effects including infusional toxicities (Mesenchymal stem cell-derived exosomes for clinical use[14]. Exosomes can be loaded with different molecules. Exosomes can carry and deliver molecules to damaged areas and may have therapeutic effect[15].

In contrast to transplanted MSCs, the MSC-derived exosomes do not proliferate, are less immunogenic and are easier to store and deliver than MSCs[16].  Exosomes have been characterized, their content was identified and studies from Prof. Offen’s laboratory at Tel Aviv University, Israel, demonstrated that they can migrate and concentrate inside inflamatory lesions and recover damaged tissues[17],[18] (see top picture below).

Many studies showed that exosomes can efficiently deliver cargo, such as drugs, to the target cell. Therefore, exosomes can be used to deliver therapeutic cargo for treatment[19].

Recently, research teams led by Prof. Shulamit Levenberg of the Technion – Israel Institute of Technology, Haifa, Israel and Prof. Offen used loaded exosomes in rats after spinal cord leasion. They demonstrated that intranasal delivery of the loaded exosomes significantly elicited functional recovery in the rats with complete spinal cord injury[20].

The capacity of exosomes to provide protection to injured tissue after stroke and respiratory distress syndrome was the subject of a recent study[21],[22]. In addition, the use of exosomes in the treatment of severe coronavirus pneumonia is also the subject of a recent study[23].

Exosomes migrate damaged areas in the brain

Brain imaging by gold nano articles

Cannabidiol (CBD)

For several years, CBD derived from the cannabis plant has been the subject of research and medicine because of its value in the treatment of many clinical conditions and its safety profile in humans. Studies have demonstrated that CBD exerts a number of beneficial pharmacological effects such as anti-inflammatory, antiemetic, antipsychotic and neuroprotective properties[24]. Moreover, studies have demonstrated that CBD treatment decreased airway hyper-responsiveness and reduced inflammation in bronchoalveolar lavage fluid. CBD treatment also decreased the inflammatory processes in a model of allergic asthma and there was an inverse correlation between CBD levels and lung function in asthmatic patients[25]. Preclinical studies showed that CBD has numerous cardiovascular benefits, including reduced blood pressure and response to stress[26].

In addition, CBD plays a crucial role in the regulation of the immune system. CBD has been tested in several animal models and has been shown to protect organs via multiple anti-inflammatory pathways. Recent publications indicate that COVID-19 affects the endothelial cells in several organs, including the lung, heart, kidney and intestine and there is evidence of direct viral infection of the endothelial cells and diffuse endothelial inflammation[27].

InnoCan’s unique, breakthrough approach to treat sever CODIV-19 patients is based on the following three (3) elements:

  1. Exosomes demonstrated benefits in many medical conditions, including the “homing” to lesions. The fact that exosomes are a thousand times smaller than cells, may allow them to easily approach endothelial infected cells and reduce the diffuse endothelial inflammation.
  2. The CBD is known for its anti-inflammatory and immune modality. Its safety profile is known and it is being used in several different clinical studies.
  3. Prof Offen has developed novel technology to load exosomes with different molecules. InnoCan in conjaction of Tel Aviv Univercity are developing a platform to allow the loading of CBD to the exosome and expects to obtain synergetic effects in coronavirus patients suffering from acute respiratory distress as well as other indications related to the central nervous system such as epilepsy and Alzheimer’s disease.

This unique approach, administrated by inhalation, targets the main infected organ directly and may be also tested for other lung infections and central nervous system diseases and disorders.

The development will involve several milestones, such as loading the chosen cannabinoids such as CBD to MSC-Exosomes and proof of concept in animal models of various diseases. Our first and immediate step will be the treatment of coronavirus patients suffering from acute respiratory distress syndrome, septic shock, or multi-organ failure.

[1] https://www.worldometers.info/coronavirus/

[2]https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167720/

[4] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext

[5] https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25728

[6] https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14830

[7] https://www.sciencealert.com/who-says-a-coronavirus-vaccine-is-18-months-away

[8] https://www.reuters.com/article/us-china-health-hospital-idUSKBN20B1M6

[9]https://www.europeanpharmaceuticalreview.com/news/116794/us-researchers-to-study-stem-cell-therapy-in-covid-19-patients/

[10]https://www.msn.com/en-us/health/health-news/cdc-director-warns-second-wave-of-coronavirus-is-likely-to-be-even-more-devastating/ar-BB1304st?li=BBnb7Kz

[11] https://www.theguardian.com/world/2020/apr/20/will-there-be-second-wave-of-coronavirus-

[12] https://thejns.org/view/journals/j-neurosurg/122/4/article-p856.xml#b70-jns14770

[13] https://www.sciencedirect.com/science/article/pii/S0006295211009531

[14] https://www.nature.com/articles/s41409-019-0616-z

[15] https://www.ncbi.nlm.nih.gov/pubmed/31454225

[16] Phinney DG, Pittenger MF. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells. 2017 Apr;35(4):851-858.

[17] Perets N, Betzer O, Shapira R, Brenstein S, Angel A, Sadan T, Ashery U, Popovtzer R, Offen D. Golden Exosomes Selectively Target Brain Pathologies in Neurodegenerative and Neurodevelopmental Disorders. Nano Lett. 2019 Jun 12;19(6):3422-3431.

[18] Betzer O, Perets N, Angel A, Motiei M, Sadan T, Yadid G, Offen D, Popovtzer R. In Vivo Neuroimaging of Exosomes Using Gold Nanoparticles. ACS Nano. 2017 Nov 28;11(11):10883-10893.

[19] Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev 2013 Mar;65(3):336-41.

[20] Guo S, Perets N, Betzer O, Ben-Shaul S, Sheinin A, Michaelevski I, Popovtzer R, Offen D, Levenberg S. Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury. ACS Nano. 2019 Sep 24;13(9):10015-10028.

[21] Otero-Ortega L, Laso-García F, Gómez-de Frutos M, Fuentes B, Diekhorst L, Díez-Tejedor E, Gutiérrez-Fernández M. Role of Exosomes as a Treatment and Potential Biomarker for Stroke. Transl Stroke Res. 2019 Jun;10(3):241-249.

[22] Horie S, Gonzalez HE, Laffey JG, Masterson CH. Cell therapy in acute respiratory distress syndrome. J Thorac Dis. 2018 Sep;10(9):5607-5620.

[23] https://clinicaltrials.gov/ct2/show/NCT04276987

[24] Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants (Basel). 2019 Dec 25;9(1)

[25] Vuolo F, Abreu SC, Michels M, Xisto DG, Blanco NG, Hallak JE, Zuardi AW, Crippa JA, Reis C, Bahl M, Pizzichinni E, Maurici R, Pizzichinni MMM, Rocco PRM, Dal-Pizzol F. Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. Eur J Pharmacol. 2019 Jan 15;843:251-259

[26] Jadoon KA, Tan GD, O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017 Jun 15;2(12)

[27] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext