Basic Science Updates for Pharmacists

Basic science is sometimes called “pure” or “fundamental” science. In this type of science, researchers attempt to understand living systems and life processes. This knowledge leads to better ways to predict, prevent, diagnose, and treat diseases and disorders. To this end, I have selected some basic science updates that may help us as pharmacists see the future potential of new drugs.

New Research Gives Clues to Artery Problems in High Blood Pressure

We have known for many years that vascular stiffening is linked to fibrosis in hypertension. However, the molecular and cellular regulation of this process has remained a mystery.

Recently, scientists in Scotland have found a small piece of genetic material called micro-RNA (specifically miR-214) which makes T-cells move to the fatty tissue around arteries cause inflammation which, in turn, produces damage to the artery structure leading ultimately to greater stiffness.¹ The higher the level of miR-214 the greater the cascade of damaging events.

This micro-RNA may represent a new biomarker for disease and a potential target for therapy.

A Functional Cure for Genetic Disease in a Single Dose

Gene therapies have been life-saving therapies. Children and babies have been given a new lease on life. Gene therapies deliver a therapeutic gene which encodes for a functional protein to cells such as in the retina or motor neurons. Could we affect all the cells in a human body with a new approach? The answer may be found in stem cells called ex-vivo lentiviral gene therapy.

This process has been used in hundreds of patients in clinical trials. Ex vivo lentiviral gene therapy works by taking the patient’s own hematopoietic stem cells and a lentiviral vector adds a therapeutic gene into each cell where it becomes integrated into the patients’ own DNA. The cells are then reintroduced into the patient and over time get into the bone marrow and proliferate.

A recent publication documented that in patients who had a genetic mutation that prevented them from producing an essential enzyme called arylsulfatase necessary to stop brain demyelination, IV infusions of hematopietic stem cells from donors allowed remyelination of these patients’ brains.² This gene therapy has the ability to address currently incurable diseases.

Treatment of Undruggable Diseases Through “Induced Proximity”

Undruggable proteins are proteins that drive disease but can’t be targeted because there is no “key-hole” or drug binding pocket. Many human proteins, approximately 85%, lack these pocket proteins. But newer cell biology using a principle called “induced proximity” maybe transforming drug design. Innate protein controllers exist in the human body that can form connections with the target protein. By forming drugs that can form connections similar to protein controllers, one can now mobilize these biological mechanisms. Examples are called proteolysis targeting chimeras which bring traditionally undruggable targets into proximity, allowing an ubiquitin-tagging enzyme to mark the target for disposal.³

Zombie Cells and Aging

Activating natural killer cells has been shown to assist in hard-to-cure blood cancers. Just turning these on may help with elimination of senescent cells responsible for many diseases of aging.⁴ This form of potential therapy may take the place of “senolytics” which are experimental drugs that destroy zombified cells that pile up and pollute tissues during the aging process.

These drugs have not proven efficacious in clinical trials, to date. The importance of addressing zombified cells in the aging process is that they are not dormant but produce toxins which can lead to inflammation potentially contributing to osteoarthritis, atherosclerosis, diabetes, and Alzheimer’s.⁵

It is important to follow new discoveries in basic science for all health care workers. The future looks very bright as we continue to innovate new potential therapies for high blood pressure, genetic diseases, undruggable diseases, and even aging.

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References:

1. Nosalski R, Siedlinski M, Denby L, et al. T-Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension. Circ Res. 2020;126(8):988-1003. doi:10.1161/CIRCRESAHA.119.315428
2. Wolf NI, Breur M, Plug B, et al. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020;7(2):169-180. doi:10.1002/acn3.50975
3. Induced Proximity. Induced proximity is why I am optimistic about treating undruggable diseases. https://www.statnews.com/2021/05/12/induced-proximity-new-ways-treat-undruggable-diseases/Accessed 05/2021
4. Shivani A, Thompson PJ, Wang Y, Koliwad S, Bhattacharya M, Bhushan A. Invariant natural killer T cells coordinate removal of senescent cells. Med 2021; 2:1-13.
5. Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes. Cell Metab. 2019;29(5):1045-1060.e10. doi:10.1016/j.cmet.2019.01.021