Syndicate content

Exosomes Are “Sensational Biological Discovery” with Fantastic Therapeutic Potential, Eminent Yale Immunologist Says in New Review

--Tiny Sub-Cellular Extracellular Vesicles Called Exosomes “Seem to Be Involved in Nearly All Biological & Clinical Processes"
--Huge Medical Potential Is Described
--Author Says Breast Milk Exosomes Are Strongly Resistant to Noxious Environment of Neonatal Stomach & Survive There for Subsequent Intestinal Absorption to Enable Genetic-Based Altering of Developing Functions in Neonates
--Data Demonstrating Successful Allergy Treatment Using Antigen-Specific, Antibody-Enabled Targeting of Acceptor Cells, Coupled with Delivery of Selected Genetic-Function-Altering MicroRNA, Is Presented

The review article describes exosomes (tiny, lipid-membrane-bounded sacs of molecular cargo) as “a sensational biologic discovery” and suggests their huge potential for enabling a wide range of major new applications, including the treatment of many different diseases, and was published online today (April 27, 2020) in Research Open—Microbiology, Immunology, and Pathology (Volume 2, Issue 1) (https://researchopenworld.com/exosome-extracellular-vesicles-a-vehicle-f...). Microbiology, Immunology and Pathology (MIP) is an open access, peer-reviewed journal with broad scope, covering all zones of Microbiology, Immunology, and Pathology.

The new open-access short review article is titled “Exosome Extracellular Vesicles: A Vehicle for Simultaneous Immune and Genetic Therapy,” and was authored by Philip Askenase (photo), MD, Professor of Medicine (Clinical Immunology) at the Yale University School of Medicine in the Section of Rheumatology and Clinical Immunology, and former Chief of Allergy & Clinical Immunology at the Yale University School of Medicine.

In his review, Dr. Askenase first described the various important physical and functional characteristics of the recently discovered exosomes and then outlined their potential utility in a wide range of important applications.

He noted that, although exosomes have only recently been discovered and characterized, they are produced and secreted by every cell type in every living thing that has been studied for them, from bacteria to humans, and they play a central role in cell-to-cell communication by virtue of their ability to transfer to targeted cells function-altering genetic-related material, often microRNAs (miRNAs), that they often carry inside special lipid membranes that protect such contents from external enzyme digestion by ubiquitous RNAases.

Dr. Askenase described exosomes as tiny, nano-sized, lipid-bounded sacs called “vesicles,” with an average diameter of 100-150 nanometers, or about one-hundredth the size of the producing cell. Exosomes are the most common subset among a large, very diverse group of vesicles called “extracellular vesicles” (EVs) that exist outside of cells.
Exosomes are present in all bodily fluids and, in humans and mice, exosomes are present in the peripheral blood at a concentration of approximately one billion exosomes per milliliter, Dr. Askenase said. White blood cells, by contrast, are present at an approximate concentration of 10,000 per milliliter. In other words, exosomes are present in peripheral blood at approximately 10,000 times the concentration of white blood cells.

MEDICAL IMPORTANCE

Dr. Askenase said that, compared to cells used for some therapies, exosomes have unusual durability, stability, resistance to noxious environments, and the ability to store biologically active genetic contents for long periods of time in the freezer and activity in vivo for at least 4-5 days after administration of a physiological dose. Exosomes are, therefore, he said, a physiological natural system for delivering genetic-related (and anti-inflammatory and anti-immunological) molecules, thus constituting new modalities for the treatment of a variety of diseases.

Dr. Askenase noted that new work in a variety of fields indicates that exosomes may be used in effective therapies for cancers, arthritis, stroke, spinal cord injury, myocardial infarction, lung fibrosis, and other diseases. He said that investigations have begun into autoimmune conditions, such as multiple sclerosis, and nervous system degenerative conditions, such as Alzheimer’s or Parkinson’s diseases, and even in autism.

NOVEL NANO-ENTITY ENABLES VESICLE-BASED THERAPIES THAT CAN ALTER FUNCTIONS OF TARGET CELLS

Dr. Askenase wrote that exosomes are a completely unanticipated nano-entity that can genetically influence production of proteins in targeted cells and thus alter the function(s) of these target cells. He noted that exosomes are the dominant mechanism for the inter-cellular transfer of genetic function, and thus have great biologic and medical importance.

He said that exosomes introduce many new possibilities, including better understanding of disease mechanisms, new ways of making diagnoses after isolation from blood and other bodily fluids (so-called “liquid biopsies”) followed by molecular analyses, and as vehicles for new natural nano-vesicle-based therapies.

With respect to the latter point, Dr. Askenase noted that exosomes have significant advantages relative to the numerous problems currently associated with designing artificial therapeutic nano-particles, which are non-specific, unable to cross tissue barriers such as the blood-brain barrier, and are rapidly eliminated by natural cellular mechanisms that detect their artificiality.

INTERCELLULAR TRANSFER OF GENETIC-ACTING MOLECULAR CARGO

Dr. Askenase stated that “the main and entirely new biologic function of exosomes is their ability to enter acceptor cells, either near or far, via the blood stream, in order to transfer the genetic-acting molecules like miRNAs that they carry.”

Exosomes can contain a variety of molecule types, including proteins, a wide variety of RNAs, and, rarely, DNA, that they can transfer to targeted cells. Most frequently, Dr. Askenase said, exosomes carry microRNAs (miRNAs), that are small polymers of RNA of approximately 22 base pairs.

MicroRNAs can bind to cytoplasmic mRNAs encoding proteins that can produce modifications of the DNA in the nucleus of the targeted cells to alter their genetic-mediated production of proteins that, in turn, alter target cell function by altering molecular and metabolic pathways of the target cells that can influence important in vivo functions.

Exosomes can be isolated from healthy individuals and easily enriched for therapeutic delivery of their selected molecular cargo to individuals with a disease, Dr. Askenase said. In addition, exosomes can, in some instances, be used across species without concern for immunologic or genetic incompatibility. The miRNAs are often universal across species. Dr. Askenase added that, because exosomes only rarely contain DNA, there is little risk of transformation to cancers.

DUAL ANTIBODY-ENABLED CELL TARGETING & TRANSFER OF GENETIC-MEDIATED, FUNCION-ALTERING miRNA--UNPRCEDENTED SIMULTANEOUS COMBINATION OFFERS NOVEL OPPORTUNITIES

In studies at his and collaborating laboratories, Dr. Askenase stated that exosomes isolated from immune or tolerized cells can bind antigen-specific antibody light chains on their surfaces and that this binding endows these exosomes with specificity for cells bearing the relevant antigen. In addition, selected miRNAs can be associated with this subset of exosomes and then be carried in these exosomes to antigen-bearing acceptor cells where the miRNAs are released into the target cell cytoplasm, where they can mediate particular genetic-based functions.

This combination of antigen-specific cell-targeting capability and the ability to deliver selected miRNAs to modify specific genetic-mediated functions is unprecedented and offers novel opportunities, Dr. Askenase said.

EXOSOME-INDUCED SUPPRESSION OF DTH IN MICE

As an example, he presented data showing that an active delayed-type hypersensitivity (DTH) reaction in the ear skin of mice with an allergy to the casein protein in milk can be successfully suppressed by the oral administration of exosomes that have been purified from suppressor T-cells, with the exosomes then being made both casein-specific by the attachment of casein-specific antibody chains to the exosome membrane, and function-altering by the inclusion in the exosome interior of miRNA-150 that the Askenase laboratory has found to be frequently involved in regulation of this family of immune responses.

Dr. Askenase stated that “to our knowledge, such chosen dual antigen-specific and selected miRNA-mediated gene-expression-altering therapy, here mediated by exosomes, has not been achieved before.”

Dr. Askenase’s data further showed that oral administration of these exosomes was superior to other routes of administration (intravenous, intraperitoneal, and subcutaneous). He added that oral administration would result in greater patient acceptance and comfort.

BREAST MILK EXOSOMES MAY BE INTESTINALLY ABSORBED BY NEONATAL STOMACH

Dr. Askenase provided a fascinating discussion of exosomes in breast milk, noting that this special fluid is loaded with exosomes carrying diverse and unusual miRNAs. These maternal, breast-produced exosomes are strongly resistant to the harsh, noxious environment of the highly acidic and digestive-enzyme-rich neonate stomach. He said that the survival of breast milk exosomes in the neonate stomach suggests that these vesicles can subsequently be intestinally absorbed by the neonate for consequent transfer of the exosomes’ miRNA cargo to the neonate in order to potentially regulate a variety of developing systems.

UNUSUAL RESISTANT MEMBRANE OF SOME EXOSOMES ALLOW SURVIVAL IN HARSH CONDITIONS THAT MAY BE TRACEABLE TO POSTULATED ANCIENT ORIGINS

Dr. Askenase said that exosomes have special membranes that contain unusual proportions of lipid components that result in high surface viscosity and rigidity. These characteristics protect exosomes and allow their survival in harsh conditions in which cells cannot survive. Interestingly, Dr. Askenase has postulated that these characteristics of exosomes are derived from their hypothesized ancient origins in the noxious primordial seas, near the beginning of biological evolution. He has proposed that some exosomes may be related to “pro cells” that existed in the primordial biologic era before the development of bacteria.

"SENSATIONAL BIOLOGICAL DISCOVERY"

In conclusion, Dr. Askenase’s short review article suggests that exosomes constitute a brave new world of cellular and molecular biology. They offer an almost unlimited range of clinical applications, many now being pursued, and some not yet imagined. They are indeed a “sensational biologic discovery.”

When asked to comment on the future of exosome studies and possible applications in medical diagnoses and treatments, Dr. Askenase said the following.

“For diagnosis, isolating exosomes from the blood is a leading form of so-called ‘liquid biopsy’ to initially diagnose and then follow frequently a variety of diseases, especially cancers like melanoma treated with anti-PDL1 therapy.”

“For treatments, as new approaches develop, exosome delivery has many advantages such as the emergence of a way to carry and conduct CRISPR/Cas9 therapies.”

MORE ARTICLE INFORMATION

Dr. Askenase’s review article can be accessed at the following link (https://researchopenworld.com/exosome-extracellular-vesicles-a-vehicle-f...).

The corresponding author is: Dr. Phillip W. Askenase, Section of Rheumatology and Clinical Immunology; Department of Internal Medicine; Yale University School of Medicine; 333 Cedar Street, New Haven, Connecticut 06520; USA. (E-mail: philip.askenase@yale.edu).

This BioQuick posting was written by Michael D. O’Neill, MA, Editor & Publisher, BioQuick Online News (http://www.bioquicknews.com). BioQuick News has recently been ranked as among “ the best biology blogs on the planet.” Mr. O’Neill can be contacted at logophile2000@yahoo.com.

[Research Open—Microbiology, Immunology and Pathology short review article] [Philip Askenase, MD] [BioQuick News]