Nature's latest report says exosomes will soon be used clinically

About 50 years ago, scientists noticed that cells in cultured fluid "shed" small sacs with unknown functions.
later studies have found that the structure, called extracellular vesicles or exosomes, carries RNA, proteins and other molecules from the initial cells to adjacent cells, playing an important role in cell communication.
from being considered a strange biological phenomenon to being used as a drug delivery vector, exosomes have attracted more and more attention.
Kalluri, a researcher at the MD Anderson Cancer Center, is a member of the field of exosomes, and while trying to uncover the biological agents associated with exosomes, he is also thinking about how to develop exosomes into a therapeutic product.
2015, Kalluri co-founded Codiak Biosciences, the first company to begin clinical trials of exosome-based therapeutics.
its leading product exoSTING consists of exosomes that carry small molecule STING excitants in the modified cavity.
, Codiak launched a Phase I/II clinical trial of exoSTING for advanced solid tumors.
's other important candidate, exoIL-12, is an engineered exosome that has been engineered to express inflammable IL-12 on its surface, and is currently undergoing Phase I clinical trials in patients with early-stage skin T-cell lymphoma. Part
Table 1 is in the process of engineering exosome therapy Source: Nature Reviews Drug Discovery Other biotechnology companies are also developing exosome therapies in different ways, utilizing different sources of exosomes, different engineering modification techniques, so that exosomes carry different loads (Table 1).
recent years, it has become clear that these biotech companies working on exosomes have attracted more and more collaborations from pharmaceutical giants.
, for example, Oxford-based Evox Therapeutics struck a partnership with Takeda in March to develop a rare disease exosome and in June with Lilly to develop an exosome therapy for neurology targets.
Boston-based company PureTech has previously teamed up with Roche to study how exosomes isolated from milk could be developed as a means of delivering nucleotide-based therapies by mouth.
, the two-year partnership ends in 2020, and PureTech is now doing the research on its own.
unique advantages of drug delivery scientists have been optimizing drug delivery systems since the 1970s.
platforms such as LNPs, polymerized nanoparticles and inordern nanoparticles are used to deliver drugs to specific cells or organs.
, more than 20 nanodynamics have been approved by the FDA, including cancer, hepatitis C and haemophilia.
most successful nanotherapys carry chemotherapy drugs and other small molecules, although polymerized nanoparticles and inorgetable nanoparticles carry multiple loads.
exosomes are similar in size to nanoparticles (about 30-150nm) and larger than AAVs. bob Langer, a chemical engineer at
MIT and a big cow in the field of drug delivery, points out that there are three key features that give exosomes an advantage over existing delivery platforms: lower immunogenicity, lower toxicity, and greater ability to cross biological barriers such as the blood-brain barrier (BBB).
because of their low immunogenicity, they may be particularly suitable for repeated dosing.
gene therapy delivered by viral vectors such as AAVs can lead to an antiviral immune response if repeated, and preclinical work has shown that the number of administrations available to patients is limited.
the same is true of nanoparticles, which the body eventually identifies as foreign.
across BBB is also a critical advantage for delivery vectors.
in a 2011 paper published in Nature Biotechnology, Matthew Wood of the University of Oxford and colleagues revealed that exosomes labeled by intravenous neurons returning to the nest can cross the blood-brain barrier in mice and deliver enough siRNA to significantly reduce the expression of BACE, a potential target for Alzheimer's disease.
based on this data, Wood co-founded Evox.
Evox is currently modifying exosomes to increase its ability to deliver siRNA through the blood-brain barrier.
Evox is also optimizing the ability of exosomes to deliver proteins or mRNAs to treat rare diseases.
, chief executive of Codiak for different applications, points out that the flexibility of the exosome platform and the ability to optimize loads for different applications are critical.
Codiak's external urology was designed so that it could be absorbed by antigen-presenting cells in the tumor, retained in the injection section, and not absorbed by the mesh endothystic system.
two leading candidates for clinical development (exoSTING and exoIL-12) have been developed to restore the immune system's ability to recognize and kill cancer cells.
the company also has other immunomodulation exosomes in the preclinical development phase.
currently focuses on using exosomes to target RAS, one of the most common mutant proteins in cancer.
Although the fastest-growing development in the RAS field is targeting small molecules of the G12C mutation, one of the most common KRAS mutations, specifically the 12-bit KRAS glycine mutation cysteine, Kalluri has set his sights on the G12D mutant.
mutation is common in pancreatic cancer.
studies have shown that the pancreas is particularly good at "absorbing" exosomes delivered intravenously, and that Kalluri's exosomes containing KRASG12D siRNA improved survival in pancreatic cancer models.
Phase I clinical trial, conducted by MD Anderson Cancer Center, has begun.
PureTech took a different approach, with the goal of transporting expression vectors (expression vectors) into gastrointestinal cells using orally delivered exosomes.
, the cells will produce therapeutic proteins in place and release them into circulation through the lymphatic system.
CSO Joe Bolen, of PureTech, believes that oral administration, because it is simple and attractive, can increase patient compliance with any drug.
, however, there is another advantage to delivering exosomes orthotics orthotics to gastrointestinal cells, namely that there are no immune cells between the starting point and the target cells.
, most intravenously delivered nanotherapy is absorbed and destroyed by phagocytosis cells in the liver before reaching other target cells.
it is also possible to use exosomes to transport more complex goods, such as proteins and antibodies.
Evox is loading their exosomes with therapeutic proteins to compensate for genetic defects in rare metabolic diseases such as urea circulation disorders.
, as a new platform, the production of exosomes is faced not only with scientific challenges, but also with practical challenges, such as the production and manufacture of exosomes.
history, scientists have purified exosomes using speeding centrifuges, a laborous and time-consuming process that cannot be used in mass production.
, Codiak has replaced super-fast centrifuges with chromatography and filtration-based technology.
is also because of the first step in production improvement, the company's leading candidate products quickly entered Phase I clinical trials.
"We thought from the start that if we didn't produce it on a large scale, it wasn't a drug.
," CEO Williams said.
also looking for production solutions earlier in the year was PureTech.
company has also developed a simple purification method that can produce enough exosomes for clinical use.
early days, PureTech was able to separate about 1,014 exosomes per week using speeding centrifugation.
, using proprietary purification methods, about 1,017 exosomes can be produced in about three days.
Bolen estimates that in clinical cases, patients need about 1,013 exosomes per dose.
In addition, it's worth noting that pureTech uses exosomes that are purified from whey, a frequently discarded by-product of cheese production, rather than from expensive mammalian cell cultures in bioreacters, and are therefore less expensive.
also reassure PureTech about the safety of exosomes from this unique source, which is inherently edible.
future, all eyes are now on Codiak and its first exosome-based therapy.
everyone wants to know if exosomes are clinically feasible.
If Codiak's candidate products prove to be safe, the exosome field will collectively breathe a sigh of relief.
will also shift to improving efficacy, improving tissue selectivity, and screening for optimal loads.
"Although exosomes are still in their early stages, I think they are exciting, " he said.
," professor Langer said.
if exosomes can effectively deliver nucleotide therapy to specific tissues, it could usher in a new era in genetic medicine, an area that has so far been hampered by delivery problems.
addition, in theory, viruses could also be "loaded" into exosomes to protect AAVs from the immune system and allow large amounts of integrated or non-integrated DNA fragments to be repeatedly drugied into specific tissues.
even antibodies that target proteins in cells could theoretically be "loaded" into exosomes.
competition in the field of exosomes is how best to use them.
most early applications focused on the delivery of nucleotide therapy, exosomes may have broader functions.
," Kalluri said.
De Fougerolles, who led Evox, says all the opportunities presented in the exosome field today remind him of RNA interference (RNAi) around 2004, when scientists were looking forward to developing RNAi therapies.
now, all industry predictions of what can be done with exosomes (such as siRNA liver delivery, safe repeat delivery of mRNA, gene editing, AAV re-delivery) have the potential to completely change these areas.
reference: 1 s Exosome-base candidates move into the clinic (Source: Nature Reviews Drug Discovery)