by Jessica Cao
“Side effects may include headache, dizziness, nausea, and vomiting, and serious, sometimes fatal allergic reactions may occur.” Most common and modern-day pharmaceuticals, such as those seen in medical advertisements, are classified as small molecule drugs (SMDs). These are defined as drugs with low molecular weight and are “capable of modulating biochemical processes to diagnose, treat, or prevent diseases”. [1] The nature of SMDs makes them particularly attractive in the pharmaceutical industry, as they can be easily manufactured and regulated compared to more complex compounds. This ease and convenience in turn lowers costs, allowing them to be more accessible and affordable for patients. [2] Unfortunately, the simple composition of SMDs typically results in a litany of unwanted side effects due to their inability to target specific protein receptors.The physiological dangers of these side effects have spurred the scientific community to discover other, potentially safer methods of drug delivery.
Among these researchers is Dr. Jerzy Szablowski, an Assistant Professor of Bioengineering at Rice University. Dr. Szablowski’s research focuses on neurotherapeutics, particularly the development of technologies that can noninvasively monitor and interact with the brain.3 One of the projects at the center of his research is gene therapy. Dr. Szablowski believes that this is a distinctly promising method of drug delivery “because it can be separated into different layers of specificity.” He states that, unlike small molecule drugs, where “everything is encoded within several atoms of the molecule”, gene therapy can be optimized for specificity and modularity. Gene therapy involves the delivery of a new gene to a cell through a viral vector and a promoter, which is a DNA sequence that helps facilitate the production of the protein encoded by the gene. This type of multifaceted system is advantageous because each component can be modified for different uses. Since the purpose of the viral vector is to deliver the gene (the therapeutic component), the vector can be modified to treat specific parts of the body without altering the treatment. Furthermore, Dr. Szablowski elaborates that “the promoter [of the gene] determines subtype, [which can] provide specificity.” Ultimately, the ability to modify each component of gene therapy without affecting the others yields greater specificity for each drug. Greater specificity allows for the avoidance of side effects resulting from non-specific binding between the drug and body receptors that are unrelated to the disease being addressed. However, assessing neurological illnesses to determine necessary treatment is often difficult, as brain biopsies are highly invasive and risky.
In order to gain a better understanding of the pathology of neurological disorders and the effects that they have on specific parts of the brain, Dr. Szablowski and his lab have employed a method of controlling and monitoring brain tissue via ultrasound. This noninvasive technique involves focusing ultrasounds on a specific part of the skull to open the blood-brain barrier (BBB) by a few millimeters. As Dr. Szablowski describes, the ultrasounds are delivered in conjunction with “a special contrast agent that is FDA-approved, [which is] basically a bubble that is encased in a lipid. Because this contrast agent has gas, it can actually become compressed or [expanded].” He further specifies that ultrasounds are essentially “an expansion and compression of a mechanical wave over time”, which pushes apart blood vessels in the brain, causing the [impermeable] junctions of the BBB to separate, and the endothelium (a thin membrane) in the brain to become more permeable. During this stage, a patient’s blood can be drawn, and a simple blood test can be used to assess their neurological condition.4 This procedure can alternatively be used to deliver therapeutic nanoparticles and proteins such as antibodies to specific parts of the brain. Although the concept of opening the BBB may sound risky, Dr. Szablowski assures that “several hours post-application, the impermeable junctions basically close up, and they become normal again.” Furthermore, little to no side effects have been observed apart from minor brain inflammation, which is easily treated with the steroid dexamethasone. Dr. Szablowski believes that this method of focused ultrasound can be used independently or in conjunction with gene therapy to ultimately become a common method of highly specific drug delivery to the brain.
Dr. Szablowski also hopes to expand on his current projects to discover novel methods of low-cost drug delivery, such as non-genetic therapy. He mentions that non-genetic therapy involves the “delivery of proteins that actually produce the drug on site, and the production of the drug on site allows it to be specific.” In other words, the biological site(s) involved with a disease are the only sites being treated, with other parts of the body remaining unaffected. Furthermore, the Szablowski lab has recently begun the Therapeutic Improvement Project, which will potentially simplify the arduous and expensive process of drug development. Dr. Szablowki says that currently, when developing a drug, “you first have to make a cell model of the drug, [then] find what receptors are responsible for the disease, then test [using a] tissue culture and mouse or larger animal, and if you're lucky and pass through all those stages, you can [use on] humans.” Unfortunately, because animals and humans are biologically different, a drug can affect each organism differently, and projects often remain “stuck” at the animal model phase. Dr. Szablowski and his lab are hoping to bypass the many obstacles of drug development by creating “a single drug [that] can treat multiple diseases by just delivering to single cells.”
Ultimately, Dr. Szablowski hopes that his research will be applied to a number of diseases—most notably neurological ones such as Parkinson’s, epilepsy, and PTSD—as opposed to a specific illness. Many of these diseases are currently difficult to assess, monitor, and treat in real time, but Dr. Szablowski believes that these minimally invasive, yet highly specific methods will eventually allow the development of therapeutic treatment with little to no side effects.
[1] Ngo, H. X.; Garneau-Tsodikova, S. What are the drugs of the future? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072476/ (accessed Feb 24, 2021).
[2] Gurevich, E. V.; Gurevich, V. V. Therapeutic potential of small molecules and engineered proteins. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513659/ (accessed Feb 24, 2021).
[3] Szablowski, J. Jerzy Szablowski: The People of Rice: Rice University. https://profiles.rice.edu/faculty/jerzy-szablowski (accessed Feb 24, 2021).
[4] Miller, B. Targeting ultrasound for noninvasive diagnosis of brain cancer: The Source: Washington University in St. Louis. https://source.wustl.edu/2020/08/targeting-ultrasound-for-noninvasive-diagnosis-of-brain-cancer/ (accessed Feb 24, 2021).