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Up until 2007, scientists from around the world did not hold a grasp of the potential within exosomes to be anything more than extracellular vesicles flooding the bloodstream. If you searched through PubMed in 2006, you would find less than 51 studies focused on exosome research. Fifteen years later and a similar search will reveal over 19,000 studies. In 2007, Lötvall conducted a milestone study that revolutionized how these extracellular vesicles are perceived. Since then, there has been no turning back.

What is behind the rise in Exosome research?

The 2007 study that Lötvall spearheaded demonstrated the therapeutic potential of exosomes in various fields. The study showed that exosomes carry disease material and are therefore valuable for spreading disease. This makes exosomes an integral part of the disease process in Cancer and metabolic conditions like Diabetes and MS.

Such revelations have triggered increased interest in these cellular entities, and scientists are now looking to understand how they can treat acute and chronic conditions by using "healthy" exosomes and at the same time "load" exosomes with drug molecules, enhancing the drug’s delivery.

What Exactly Are Exosomes?

Exosomes are lipid-layered extracellular vesicles ( ∼ 30–140 nm) secreted in most cells. They contain specific lipids, proteins, and RNAs from the cells where they originate and can deliver cargo to other cells in the body. They have the ability to cross the blood-brain barrier and to deliver drugs into hard-to-reach cells, thereby optimizing treatment. It was shown also that some types of exosomes are targeting specific organs in the body or disease conditions, such as Inflammation and Cancer and since they are containing different unique characteristics, they each have their own therapeutic potential.

Scientists are therefore curious about the cargo contents of exosomes and their potential in disease detection and treatment. They are also looking into their possibility in drug delivery because they can travel through the extracellular fluid to deliver cargo to cells with a high degree of specificity and efficiency.

Researchers Are Interested in the Therapeutic Potential of Exosomes

Exosomes have potential applications as biomarkers of disease and as drug carriers. Researchers are looking to exploit the loading mechanisms of exosomes.

How Cancer starts and develops is a complicated process. Cancerous tumors release exosomes whose cargo serves as a catalysator in Cancer progression. Once released from the cell, the exosomes are transported through the extracellular fluid to the target cells. The exosome lipid bilayer protects the exosomes from degradation by extracellular enzymes. At the target cells, the exosomes create a suitable microenvironment for Cancer proliferation. Given the involvement of exosomes in Cancer pathogenesis, researchers are exploring the potential of these vesicles in molecular therapy for Cancer.

Understanding exosome biology may help in the early detection of Cancer which would, in turn, improve prognosis and enhance the survival rate.

The potential of exosomes in treating metabolic conditions is also a subject of much research. One study showed that the miRNA contents of exosomes found in patients with type 1 Diabetes are different from those found in a healthy control group. The researchers concluded that exosomes might have a role to play in the pathogenesis of type 1 Diabetes.

Exosomes have also been implicated in Alzheimer's disease; the tiny vesicles transport amyloid-β, which forms plaque in the brains of people with Alzheimer's disease. If they can carry disease molecules, scientists have been compelled to think that they might also make molecules that stop the disease.

Some forward-thinking companies are looking into ways to exploit the therapeutic potential of exosomes in the fields of biogenesis, therapeutic applications, and bioengineering. This opens great doors for improved drug delivery and treatment modalities for acute and chronic conditions.

Out of almost fifty companies currently in the space, seven are conducting ground-breaking research that can revolutionize exosome-based therapies. Below is a breakdown of what these pace-setting companies have been up to.

1. Innocan Pharma (CSE: INNO): Improving the Bioavailability and therapeutic potential of CBD Through Cutting-Edge Technology

Innocan is a pharmaceutical company committed to the development of cannabinoid integrated drugs and enhancing the targeted loading and delivery of cannabinoids such as cannabidiol (CBD). It is developing promising nanocarriers for drug delivery and targeted therapy.

The therapeutic potential of CBD is of great interest to researchers and clinicians. Unfortunately, the bioavailability of oral CBD is minimal ( 4%- 20% ) making it challenging to adequately dose CBD. Innocan is developing a wide range of OTC drugs as well as CBD-loaded liposome to be given by injection and CBD-loaded exosome, to reach targeted delivery of the CBD combined with the therapeutic potential of the exosomes. Innocan filed more than 10 patents already and the research activity is conducted at Tel Aviv University and the Hebrew university labs.

CBD has a key role in a lot of different aspects in body function, including anti-inflammatory activity, immunomodulation, Central Nerve System (CNS) activity and more. Innocan, together with Tel Aviv University is developing CBD-loaded exosomes to target different diseases, most of them are related to inflammation and CNS indication, in view of creating synergy between the healing properties of CBD and the unique potential of exosome-targeted delivery and potential therapeutic effect.

Given the current interest in cannabinoid-based therapies and the inherent challenges in maximizing bioavailability, Innocan's invention is bound to be a game-changer that will scale CBD applications.

2. Evox Therapeutics: Exosome Based therapy for ASL Deficiency

Evox Therapeutics is a leading biotechnology company that is focused on creating transformative exosome therapeutics. They have harnessed exosomes capabilities to improve the delivery of a variety of drugs to the brain across the blood-brain barrier. In 2019, Evox spearheaded research into the therapeutic potential of exosome-based therapies for Argininosuccinic aciduria is a rare genetic disorder characterized by the deficiency or lack of the enzyme arginosuccinate lyase (ASL). in an animal model study. The results demonstrated that repeated administration of protein ASL-loaded exosomes resulted in marked improvement in the survival of ASL-deprived mice.

ASL deficiency is a rare genetic disorder that is characterized by the accumulation of ammonia in the body. Being a hard-to-treat condition, the research by Evox is a much-welcomed development.

Evox, which has partnerships with Oxford University and the Karolinska Institute, is committed to exosome engineering. They are exploring different facets of exosome-therapy including protein and RNA engineering as well as targeted drug delivery. This is key in developing potent exosome therapeutics that harness the native properties of exosomes and the specificity of conventional biologics.

Back in 2020, Evox collaborated with Takeda to utilize Evox’s exosome technology to treat a variety of brain-related syndromes, in a close-to 1B USD investment. Moreover, later that year Evox joined hands with Eli Lilly (NASDAQ: LLY) in a joint effort to apply exosome technology to the delivery of RNA interference and antisense oligonucleotide drugs, to reach the central nervous system targets. The entire investment made to the project is estimated to be around 1.2B USD.

In May this year, Evox made presentations at the 24th annual meeting of the American Society for Gene and Cell Therapy (ASGCT) using their proprietary DeliverEX platform. The presentation highlighted advances on the platform in regard to advancing exosome-based therapeutics. This definitely makes Evox a leader in developing next-generation exosome-based therapeutics.

3. Codiak’s engEx Platform

Codiak is a biotechnology company that is engineering exosome-based biologic medicines. The engEx platform allows for the development of engineered exosomes with predictable and reproducible therapeutics. The platform enables the designing of unique exosomes that are loaded with therapeutic molecules. This makes way for selective or targeted drug delivery to optimize treatments for a wide range of conditions with high unmet medical needs. This is a breakthrough platform that is likely to enhance the scalability of exosome-based therapies.

They are currently conducting phase one oncology trials on the platform. These trials are focused on engineering exosomes therapies that are targeted at different types of cancers such as Kaposi’s sarcoma, melanoma, and GBM. They are also conducting neurology studies which are currently in the discovery phase.

In May this year, Codiak made a couple of presentations at the annual convention of the American Society for Gene and Cell Therapy (ASGCT). One presentation demonstrated that their proprietary exosome-based vaccine platform (Exovacc) could induce antigen-specific immune responses in animal models. A different presentation demonstrated the potential of engineered exosomes to target neuronal cells (exosome tropism). Codiak’s commitment to science is clearly evident through these studies.

4. Stem cell Medicine Ltd.: Exosome Research for Autism

This is a biotechnology company focused on developing second-generation cell therapy products designed to address neurological indications, such as multiple sclerosis, pain, and neuromuscular injuries. In 2019, they rolled out a study to investigate the potential of exosomes in treating autistic spectrum disorders (ASD). This group of neurodevelopmental disorders manifests with symptoms including impaired social interaction, poor communication skills, repetitive behaviors, and cognitive impairment.

Mouse models displaying autistic-like behaviors were evaluated in this study; BTBR and Shank 3. The mice were given intranasal exosomes (MSC-Exo) derived from bone marrow or adipose tissue. The results showed a positive effect with no harmful side effects observed. More extensive randomized clinical trials will paint a clearer picture of the efficacy of exosome-based therapies for managing ASD.

Stem Cell Medicine's technology for the treatment of autism is based on stem cell-derived exosomes delivered through the intranasal route. Cases of ASDs in children have been on the rise in the recent past. To date, there is no effective treatment for this spectrum of disorders. Stem Cell Medicine collaborates with Tel Aviv University and other academic institutions to advance the course of exosome research.

5. Aethlon Medical, Inc: Hemopurifier for the Treatment of Metastatic Cancer

Aethlon Medical is committed to groundbreaking research in global health and biodefense. They have recently focused their energies on researching the potential of tumor-derived exosomes in cancer therapy. To achieve this, they designed a technology (hemopurifier) to capture the exosomes from tumors of different cancers such as breast, ovarian, and cancerous melanomas. Currently, they are conducting an early feasibility study to investigate the usefulness of hemopurifier plus pembrolizumab (Keytruda) in treating advanced or metastatic cancer of the head and neck. This study lays an excellent foundation for future research in this area.

In June this year, Aethlon Medical published the results of a study where they were investigating the safety and potential of the hemopurifier in managing two critically ill COVID-19 patients. The hemopurifier was able to filter out viral-related exosomes in one of the patients. A study in December 2020 demonstrated the effectiveness of hemopurifier in removing cancer-associated exosomes. This company is making great strides in developing exosome-based therapies for the suppression of cancer and viral diseases.

6. MDimune Inc.: Non CBD-Exosome Research for Targeted Drug Delivery

This company is looking to exploit the potential of extracellular vesicles (exosomes) in enhancing targeted drug delivery. They have created an innovative tech-based platform called BioDrone to optimize the mass production of next-gen drug delivery systems. BioDrone is patented in various countries, including the US, UK, China, Korea, and Japan. The researchers believe that this technology has enormous therapeutic potential in maximizing the efficacy of biomolecular drugs while minimizing the side effects.

7. Ilias Biologics Inc.: Researching Exosome Loading

Through its latest technology EXPLOR, Ilias is creating ways to actively load proteins into exosomes with a high level of efficiency. For example, some exosomes are loaded with anti-inflammatory proteins that target inflammation signaling pathways in cells. This potential can be harnessed in the treatment of inflammatory conditions. Non-clinical studies have shown high efficacy of exosomes in managing inflammatory and metabolic disorders as well as cancers. Ilias recently initiated clinical trials to investigate the loading of antibodies targeting oncogenic proteins to inhibit the progression of metastatic tumors. They are currently working on loading gene-editing proteins into exosomes.

In August this year, Ilias published a review paper titled "Biodistribution of Exosomes and Engineering Strategies for Targeted Delivery of Therapeutic Exosomes." The paper reviewed the properties of exosomes and their ability to be engineered to target specific cells and organs. They were recently granted a license for their EXPLOR platform in China and Japan. Through this patent, they have managed to secure four additional EXPLOR patents in other countries including the US and Korea.

Exosome-CBD Innovation is Bound to be a Gamechanger

The cannabis industry is fast embracing nanotechnology. Through leading innovation, the industry is setting the stage for significant transformations. Newly developed technologies can harness the synergistic benefits of CBD by optimizing bioavailability and drug delivery to hard-to-reach cells.

This will be a game-changer because it will impact the various aspects of the CBD market: efficacy, dosing, safety profile, costing, and profitability for businesses with vested interests in the space. A better delivery system and increased efficacy will help to achieve the full potential of the legal cannabis industry, which was valued at $9 billion in 2020. The same technology can be applied across the board to increase the bioavailability, efficiency, and drug delivery of other therapeutic compounds.