Tag: #liveforever

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mRNA: the therapeutics of the future! (or, 2021 the way research is going…)

Today’s top selling drugs are mostly biologics, which means proteins (e.g., monoclonal antibodies) being used as medicine. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018, and is expected to generate revenue of $150 billion by the end of 2019, and $300 billion by 20251. Thus, the market for therapeutic antibody drugs has experienced an explosive growth with new drugs being approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases, which have increasingly fewer adverse effects due to their high specificity. 

But, these types of treatments carry their own limitations. Besides of a long period of development, they can only access the extracellular space, the serum. Yet, ~2/3 of the human proteome are intracellular or transmembrane proteins; which means that biologics cannot treat disorders that are caused by these types of proteins. 

As such, an alternative mechanism to make these proteins is needed in order to go further in the advancement of therapeutics. 

One such mechanism, is to supply the mRNA that encodes that protein. As such, any protein can become a drug. And, since only the coding region varies from mRNA-drug to mRNA-drug; once the delivery vehicle problem is resolved (e.g., using lipid nanoparticles), the development of new mRNA drugs should be quite fast in comparison with other types of medicine.

The other positive aspect of mRNA as therapeutics, is that it can be used in many different types of modalities: prophylactic vaccines, cancer vaccines, intertumoral immune-oncologicals, localized regenerative therapeutics, systemic secreted medicine, and cell surface therapeutics…

Another positive aspect of mRNA-drugs is that several mRNAs can be delivered at once, like in the case of prophylactic vaccines (e.g., Moderna Therapeutics Cytomegalovirus (CMV) mRNA vaccine delivers 6 different mRNAs to encode a multiprotein complex). 

Or, another possibility, is the personalization of cancer vaccines, where different patient-specific neoepitopes are sequenced, and mRNA is created that encodes those 20-35 specific tumour-neoepitopes. 

Those mRNAs can also encode cytokines, that are able to boost the immune system to attack a tumour, like intertumoral immune-oncologicals therapeutics. 

In the field of localized regenerative therapeutics, there is currently a project between Moderna Therapeuticsand AstraZeneca in Phase II clinical trials, where Vascular Endothelial Growth Factor-A (VEGFA) mRNA is injected NAKED, without lipid nanoparticles, directly into the heart muscle of patients with a recent Myocardial Infarction (MI) to help rebuild blood vessels. 

Of course, many challenges still exist. 

mRNA needs to be rightly sequenced and be made at high purity. It also needs to have the ability to avoid the innate immune sensors, like Toll-like receptors (TLR) in the endoplasmic reticulum, and RIG-I/MDA-5-like receptors in the cytoplasm. What researchers do to avoid the first ones (TLRs) is to use a Pseudouridine, which looks like a Uridine and still base-pairs, but escapes TLR recognition. To avoid the RIG-I/MDA-5-like receptors, researchers need to highly purify the therapeutic mRNA, so that no double-stranded RNA exists (or, reengineer T7 RNA polymerase not to produce dsRNA at all).

The next step on making a good mRNA-drug is to find an efficient delivery method. For that, most therapeutics will need some sort of mRNA encapsulation with Lipid nanoparticles, which are akin to endogenous lipid transport complexes, similar to Very-Low Density Lipoproteins (VLDLs).

Finally, in order to make a good mRNA-drug, there needs to be knowledge on how to engineer the best mRNA sequence for a particular purpose. As such, there needs to be translation initiation fidelity, so that it always starts in the right place and there’s faithful decoding; and, also, the ribosome needs to stop in the right place. There needs to be high translation efficiency, a functional mRNA half-life, and hit the correct cell type, by putting off-logic gates, like microRNAs target sites in the 3’prime UTR and causing the mRNA to be degraded in case it hits an undesired cell type. Also, the mRNAs need to be tailored to the protein type (e.g., secreted, mitochondrial).

So, let’s see what the future brings from mRNA therapeutics…

References:

1          Lu, R.-M. et al. Development of therapeutic antibodies for the treatment of diseases. Journal of Biomedical Science 27, 1, doi:10.1186/s12929-019-0592-z (2020).

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Personalized Cancer Vaccines: the future is here!

In humans, anti-tumour immunity is usually very effective, because our T-cells (a type of a white blood cell) can detect the presence of specific cancer neoantigens. These are short chains of aminoacids (peptides) that appear due to tumour-specific mutations, and mark the cancer cell as foreign. They are highly immunogenic, because they are not present in normal tissues; and therefore, evade central thymic tolerance and activate our immune system to destroy them.

Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their efficient discovery and evaluation only became possible recently, with the availability of massive parallel sequencing for detection of all coding mutations within tumours; and, of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. 

It has been shown that vaccination with these specific neoantigens can expand the pre-existing neoantigen-specific T-cell populations; and, induce a broader repertoire of new T-cell specificities in cancer patients. This can actually tip the intra-tumoral balance, in favour of an enhanced tumour control. 

Research studies now demonstrate the feasibility, safety, and immunogenicity of vaccines that target up to 20 predicted personal tumour neoantigens (e.g., Melanoma Neovax anti-PD11). Vaccine-induced polyfunctional CD4+ and CD8+ T-cells can target unique tumour neoantigens; and, not only that, these T-cells can have persistent memory. This because, studies from the Dana-Farber Cancer Institute and Dr. Catherine Wu’s lab, show that patients have a continuous response 5-7-years later after the initial vaccination, with a second-wave of immune response that shows epitope spreading from the initial epitope. What this means, is that the patient immune system was able to recognize and target tumour cells, even when they try to disguise themselves years later.

Researchers have gone further: at Genocea Biosciences they are developing precision neoantigen selection with their branded ATLAS platform. They can optimize the set of neoantigens for inclusion in the vaccine, by excluding inhibitory antigens (called Inhibigens) that suppress the patient’s immune system, blocking the internal growth of the tumour cells.

Neoantigen

References:

1          Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217-221, doi:10.1038/nature22991 (2017).

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Stroke or heart infarct?

According to a recent study by Daghlas and colleagues1, compared to sleeping 6 to 9 h/night, short sleepers have a 20% higher risk of having a heart attack; but, if you are a long sleeper (i.e., sleeping >9h/night), than your chances are even worse, because your risk increases to 34%. Even though the researchers don’t know the underlying cause for such susceptibilities, they claim sleeping too much or too little boosts inflammation in the body, which is associated with the development of heart disease. If you have a genetic predisposition for heart disease, this study found that sleeping between 6-9h, actually reduces your risk of having a heart attack by 18%, which is actually very good news, since not only diet and exercise can help you keep your heart healthy. More and more data, supports the evidence that we should consider sleep to be an adjustable and controllable risk factor for our good heath status2.

Speaking of diet, another study published recently in the Journal of the American Heart Association by Hyunju Kim and his team3, showed that healthy plant‐based diets, which are higher in whole grains, fruits, vegetables, nuts, legumes, tea, and coffee, and lower in animal foods, were associated with a lower risk of cardiovascular disease mortality and all‐cause mortality. Of course, they didn’t explore if the quality of plant foods (either healthy plant foods, or less-healthy plant foods) within the “framework of plant‐based diets” would be associated with cardiovascular disease and all‐cause mortality in the general population.

But, what is intriguing is that, another recent study by Tammy Tong and colleagues4, examined the associations of vegetarianism with risks of ischemic heart disease (i.e., coronary artery disease) and stroke. The results of this study showed that vegetarians had 20% higher rates of total stroke than meat eaters – which was equivalent to 3x more cases of stroke over 10 years; and, the associations for stroke did not soothe after adjustments to other disease risk factors. As the authors of the study say, vegetarian and vegan diets have become increasingly popular in recent years, partly due to perceived health benefits, as well as concerns about the environment and animal welfare; but, what the evidence suggests, is that vegetarians might have different disease risks compared with non-vegetarians. The study group of vegetarians and vegans in this cohort had lower circulating levels of several nutrients (e.g., vitamin B12, vitamin D, essential amino acids, and long chain n-3 polyunsaturated fatty acids), and differences in some of these nutritional factors could contribute to the increased stroke risk. Not only that, but a number of studies in Japan5, 6, showed that individuals with very low intake of animal products, also had an increased incidence and mortality from hemorrhagic and total stroke, implying that some factors connected with animal food intake might be protective for stroke. 

Its like Yin and Yang from ancient Chinese philosophy. Rather than opposing, or standing at the sides, our health and life is made of complementary forces that interact to form a dynamic system. It’s all about balance and balancing the sides (and diets).

All in life is balance
Balancing life’s way

References:

1.         Daghlas I, Dashti HS, Lane J, Aragam KG, Rutter MK, Saxena R and Vetter C. Sleep Duration and Myocardial Infarction. Journal of the American College of Cardiology. 2019;74:1304-1314.

2.         Tobaldini E, Fiorelli EM, Solbiati M, Costantino G, Nobili L and Montano N. Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. Nat Rev Cardiol. 2019;16:213-224.

3.         Kim H, Caulfield LE, Garcia-Larsen V, Steffen LM, Coresh J and Rebholz CM. Plant-Based Diets Are Associated With a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All-Cause Mortality in a General Population of Middle-Aged Adults. J Am Heart Assoc. 2019;8:e012865.

4.         Tong TYN, Appleby PN, Bradbury KE, Perez-Cornago A, Travis RC, Clarke R and Key TJ. Risks of ischaemic heart disease and stroke in meat eaters, fish eaters, and vegetarians over 18 years of follow-up: results from the prospective EPIC-Oxford study. BMJ. 2019;366:l4897.

5.         Kinjo Y, Beral V, Akiba S, Key T, Mizuno S, Appleby P, Yamaguchi N, Watanabe S and Doll R. Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan. J Epidemiol. 1999;9:268-74.

6.         Sauvaget C, Nagano J, Allen N, Grant EJ and Beral V. Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study. Int J Epidemiol. 2003;32:536-43.