- #1 Alternative Therapy for Pain: Fighting the Opioid Crisis
- #2 The Advent of AI in Healthcare
- #3 Expanded Window for Acute Stroke Intervention
- #4 Advances in Immunotherapy for Cancer Treatment
- #5 Patient-Specific Products Achieved with 3D Printing
- #6 Virtual and Mixed Reality for Medical Education
- #7 Visor for Prehospital Stroke Diagnosis
- #8 Innovation in Robotic Surgery
- #9 Mitral and Tricuspid Valve Percutaneous Replacement
- #10 RNA-Based Therapies
#1 Alternative Therapy for Pain: Fighting the Opioid Crisis
Nearly 116 people die every day from opioid-related drug overdoses. Declared a public health emergency by the Department of Health & Human Services in 2017, the opioid crisis has taken the country by storm with misuse of prescription painkillers on the rise.
Today, a large number of patients prescribed opioids for chronic pain abuse the drugs in some way. Opioids, the highly addictive class of drugs used to treat pain, are often exploited for the sense of wellbeing or euphoria they elicit. As with any addiction, opioid addiction is known to affect patients from all walks of life.
Unfortunately, opioid addiction is widespread, and it is not unlikely to have already affected someone you know. Whether it be in a friend, neighbor, or coworker, the dependence that stems from abuse has the ability to permanently ruin lives and relationships.
Aside from the clear detriment to public health, this national crisis wreaks havoc on social and economic welfare. To date, the economic cost of the opioid crisis is an estimated $1 trillion. Through 2020, the crisis is projected to cost the United States an additional $500 billion if the burden continues at current rates.
The opioid crisis has been known to effect each region of the nation to varying degree. The rural Midwest (Ohio, Michigan, Indiana, Kentucky, and West Virginia) has suffered greatly. Ohio, in fact, ranks as one of the top five states for opioid-overdoses.
However, there is hope. According to Ohio Department of Health, in 2017, Ohio experienced an 8-year low in prescribed opiate-related deaths. Ohio has also seen a drop in opioid prescriptions for a fifth straight year, and a 28 percent fall in the number of opioids dispensed to Ohio patients. The reduction in opioid prescription noted in Ohio is due in part to the integration of alternative therapies for pain.
For some time, there’s been talk of pain management with various natural remedies. Electrical stimulation therapy, aroma therapy, stress management, food therapy, and magnetics have all been explored with varying levels of validity and success, but these therapies have not answered the call of the crisis. The true innovation in pain management lies in a new approach to opioid prescription. Pharmacogenomics, the study of how genes affect a person’s response to drugs, is an excellent tool to individualize the prescription of medications for pain. Just as one’s genetics influence, for example, eye, skin, and hair color, so too do genetics determine an individual’s ability to metabolize drugs effectively. The field of pharmacogenomics seeks to apply an individual’s genetics to lead to the most rational and tailored administration of medication.
As an example, codeine is metabolized by most individuals into morphine, thus providing pain relief. Individuals whose genetic makeup, however, is such that they will metabolize codeine rapidly may suffer an adverse, possibly fatal, drug reaction. Furthermore, those whose genetics dictate that they are poor metabolizers of codeine will get inadequate pain relief. They may therefore use up their prescriptions too quickly and be labeled as “drug-seeking” when they return for a prescription too early. Or, perhaps worse, they may stop taking the codeine that is ineffective for them, their pain persists, and the unused drugs may find their way to the streets. The same gene that controls codeine metabolism also controls the metabolism of tramadol, hydrocodone, and oxycodone – other opioid drugs.
In these examples, pharmacogenomics can be used to guard against potentially dangerous adverse drug reactions, to eliminate the stigma that may be ascribed unfairly to some based solely on their genetics, and to uncover an effective treatment for each patient’s pain. These different metabolizer states can be tested for quickly in the clinical laboratory before a prescription is written for a patient with pain. Test results can then be used to write a prescription more specifically suited to that patient based on his/her pharmacogenetics, an excellent example of precision medicine.
In 2019, with increased access to genetic testing, pharmacogenomics is poised to make significant inroads into precision medicine. Since its inception, pharmacogenomic testing has seen modest integration into clinical practice. But with its applications for pain, an uptick is expected in the wake of the crisis. Nationwide, healthcare professionals are working hard to make pharmacogenomic testing an integral part of caring for patients and their pain, so we may do all we possibly can to one day vanquish the opioid crisis.
#2 The Advent of AI in Healthcare
In this age of technology, it has been made clear that artificial intelligence knows no bounds. From gaming to the automotive industry, AI has shown its creativity and usefulness time and again. Once thought of as a futuristic threat to humankind, artificial intelligence is now a part of everyday life. The exact opposite of a threat, artificial intelligence is changing and saving lives while being woven tighter into the fabric of society.
In healthcare, AI is changing the game with its applications in decision support, image analysis, and patient triage. To enhance artificial intelligence technology, universities, tech companies, and venture capital firms alike have invested millions over the years. Now able to process unlimited amounts of unstructured data (notes from exams, scan images, etc.), AI programs turn images and words into intelligible information. Analysis and organization of this raw data is helping healthcare professionals better interpret patient data and deliver superior care.
With its image analysis programs, AI technology is taking the hassle and uncertainty out of viewing patient scans. Today, machine learning algorithms have the ability to highlight problem areas on images, aiding in the screening process. This image analysis from the computer serves as an additional degree of confidence in the diagnosis of a patient’s condition. This technology has seen greatest adoption in fields such as dermatology, neurology, and ophthalmology, but its specialty reach has expanded with time.
Decision support is another application in which AI is improving patient outcomes. When faced with a difficult case file, even the most experienced of physicians may have trouble suggesting next steps for a complicated patient. For this reason, clinical decision support systems are becoming essential tools for healthcare providers. With their ability to reduce clinical variation and duplicative testing while ensuring patient safety, decision support systems quickly make sense of the mountains of data within a physician’s EMR system.
Also popular for patient triage, AI is helping with the issue of physician burnout by providing a safe and reliable method of automated outreach to patients. To avoid unnecessary patient visits for trivial or nonexistent conditions, AI is being deployed to collect patient data. Via an app or text messaging, chatbots can now ask patients a series of questions regarding their symptoms. After collecting sufficient information, the automated bots are able to recommend a visit to the doctor, or send along the information for physician review and consultation. AI’s patient triage application is taking the guesswork out of self-diagnosis and saving both the patient and healthcare provider time and money. With AI’s continued integration into healthcare, caring for patients has become a matter of working smarter, not harder.
#3 Expanded Window for Acute Stroke Intervention
You rise in the dead of night to your loved one behaving strangely. The signs of a stroke are serious and terrifying: weakness in half the body, trouble producing and understanding speech, and altered vision. Immediately you recognize something is wrong, but can the wrong be righted? You fear too much time has passed and that the disability may become permanent. You find yourself asking “What if I had just woken up sooner?”
When it comes to the intervention of a stroke, a timely manner can mean the difference between life and death. With stroke, blood flow is interrupted to a portion of the brain. Depriving the brain’s neurons of nutrients and oxygen, stroke prevents proper functioning and causes damage to the brain’s ever fragile tissue. With a death rate of two million brain cells per minute, prolonged lack of blood flow can cause irreversible destruction resulting in loss of brain function and disability.
When caused by a blood clot in the brain vasculature, and caught early, a stroke is often able to be treated with clot removal techniques before significant death of tissue occurs. Medical professionals can de-clot with the intravenous administration of emergency stroke drug, tPA, or with a procedure known as a mechanical thrombectomy. In a mechanical thrombectomy, a neurovascular device is deployed within the blood vessels of the brain, and used to physically grab and remove, or vacuum out, the bedeviling clot. These methods of intervention have been used for some time.
Intervention, however, is only recommended within a limited time frame. Dubbed the “golden window,” the six hours after stroke onset were once thought to be the period of time during which intervention was most effective at minimizing or preventing damage. Intervention rarely occurred outside the window, and patients who arrived late to the hospital were often left with clots, tissue death, and impairment. However, new research suggests that the window for intervention may be larger than previously advised.
New guidelines released by the American Heart Association and American Stroke Association in January 2018 recommend an increased treatment window for clot removal up to twenty-four hours post-stroke. The recommendations came in light of results of the DAWN and DEFUSE 3 trials; trials which illustrated the benefit of mechanical intervention up to 24 hours after onset of stroke.
The expanded intervention window is anticipated to lower the risk of disability for an astounding number of future stroke patients who would not have been treated following previous guidelines. Though time remains of the essence for the treatment of stroke, this expanded window gives hope to loved ones who fear they weren’t quick enough.
#4 Advances in Immunotherapy for Cancer Treatment
In the practice of word association, the mention of “cancer” might bring to mind “chemotherapy.” Thought to go hand-in-hand for decades, chemotherapy has been used to blast cancer cells for nearly 60 years. While chemotherapy is generally largely successful, it is often ineffective or minimally effective in a subset of cancers. With the use of genetic testing technologies on the rise, new, highly personalized therapies for cancer come into play. These therapies, dubbed “immunotherapies,” have advanced exponentially since their discovery.
Cancer immunotherapy, or biologic therapy, is a technique that uses the body’s own immune system to fight cancer. Immunotherapies boost the body’s natural defenses and work to either stop/slow the growth of cancer cells, prevent cancer cells from spreading, or destroy cancer cells all together. Immunotherapies exploit the fact that cancer cells are often recognizable to the immune system via molecules on their surface. With this mechanism of recognition, immunotherapies are highly selective and efficient at identifying and destroying tumor tissue. Immunotherapies can be either passive or active, and are split into several classes including cellular immunotherapies, antibody therapies, and cytokine therapies.
While immunotherapies for cancer have existed for some time, the worldwide work toward a cure for cancer continues to highlight new and novel immunotherapeutic targets. To healthcare professionals, the past two years stand out as the season in which immunotherapy became a household name. During this period, the market for immunotherapeutic cancer therapies has seen an unprecedented number of FDA approvals. In 2019, the number of agents available to patients will only continue to grow.
Today, one of the most notable advancements in cancer immunotherapy is its simultaneous use with cytotoxic therapy. Known as “joint therapy,” the integration of immunotherapy and cytotoxic therapy (chemotherapy) has been studied in several patient populations with great success. In a sample of patients with metastic, nonsquamous, non-small cell lung cancer, joint therapy has been incredibly effective – more than doubling the cancer response rate from its rate with chemotherapy alone. In 2017, the FDA approved the first combination of chemotherapy and immunotherapy for patients of this cohort.
Checkpoint inhibitor therapy is another immunotherapy changing cancer treatment. The therapy targets immune checkpoints, key regulators of the immune symptom, which tumors can use to protect themselves from attacks by the immune system. In blocking inhibitory checkpoints, immune system function is restored. Voted our #6 medical innovation in 2015, immune checkpoint inhibitor therapy has made great progress since then. Recent studies show the production of significant, durable responses with these therapies. In October of 2018, immunotherapy pioneers James P. Allison and Tasuku Honjo were awarded the Nobel Prize in Physiology or Medicine for their research of the science behind checkpoint inhibitor therapies.
Other innovations on the immunotherapy front involve therapies derived from T-cells. Following hot on the trail of the wildly successful CAR-T cell therapy, new forms of engineered T-cells have exhibited enhanced anti-tumor activity and selectivity in a variety of cancers. T-cells are a subtype of white blood cell that play a central role in cell-mediated immunity. Produced in the thymus, T-cells acquire antigen receptors that enable them to identify foreign substances in the body. In engineering these receptors, T-cell therapies are able to recognize specific target antigens on tumor cells allowing the body’s immune defenses to attack the cancers within a patient.
In early 2018, engineered T-cell technology gained popularity with the kickoff of several clinical studies for its use in new types of cancer. This popularity is expected to grow in the coming year. The agent with the most promise in 2019 is that of a T-cell receptor (TCR-T) therapy developed for use in liver cancer – the world’s third most deadly. With the near daily discovery of new immunotherapeutic targets, it is the hope that effective therapies will soon exist for all tumor profiles.
#5 Patient-Specific Products Achieved with 3D Printing
In 2018, everything is tailor-made. From your morning cup of coffee to your workout playlist, things are exactly the way you like them and made for you. With all things customizable, society is shifting its focus to personalization within healthcare. Utilizing 3D printing technology, medical devices are now matched to the exact specifications of a patient. Designed to be more compatible with a patient’s natural anatomy, devices modeled from patient images have shown greater acceptance by the body, increased comfort for the patient, and improved performance outcomes. The versatility provided by 3D printing gives medical practitioners the ability to give patients the most advanced care, while simultaneously minimizing their risk of complication.
New and noteworthy work in this space includes customized airway stents for diseases narrowing the airway, external prosthetics, and cranial/orthopaedic implants. Customized airway stents are currently in limited production and have been implanted in a small population of patients under compassionate use protocols. Data from these individuals support the practice of customization with significant improvements seen in both function and quality of life. FDA approval for the stents is expected in 2019. Work in prosthetics and other bodily implants is also gaining speed with some cleared for the commercial market.
3D printing technology has also been found helpful in the realm of surgical planning. For surgeries that are new or complex in nature, significant measures must be taken to ensure comprehension of the case. Proactive printing of a patient’s anatomy as a visual aid has been found useful in the preparation for difficult surgeries. The ability to hold a physical model of the patient’s anatomy gives surgeons the ability to conceptualize the ideal course of action prior to operating. To date, the technology has been used for many complicated heart surgeries, and even the Cleveland Clinic’s most recent total face transplant. With its widening healthcare applications, 3D printing is increasing the attention to detail in patient care.
#6 Virtual and Mixed Reality for Medical Education
You are strapped in a roller coaster car approaching the top of a steep hill. Your palms begin to sweat and your heart races. As the front of your car dangles over the edge and plunges to the valley below, your stomach drops – the scene feels like complete reality. When the ride is over and you remove your goggles, you remember that you are not at the amusement park. The ride you’ve just experienced was completely virtual, but it felt eerily real.
Virtual reality, or VR, is the use of computer technology to create a simulated environment. Different from traditional user interfaces, virtual reality immerses the user inside an experience. In a virtual reality simulation, users are able to interact with the 3D world before them as if they are a part of it. VR stimulates the senses to transport the user to an artificial world and provide an experience that mimics the experience in real life. A headset is the device commonly used to experience said virtual reality.
Mixed reality, or MR, is the use of computer technology to merge real and virtual worlds to create a new hybrid environment. In this hybrid environment, physical and digital objects co-exist and interact in real time. Mixed reality technology anchors virtual objects to the real world allowing users to interact with them. Mixed reality is often brought about through the use of glasses and a controller.
The abstract concepts of virtual and mixed reality have dazzled audiences for quite some time, but with improving technology, access to the concepts is greater than ever before. VR/MR technology are now commercially available for several applications and play a great role in many fields. Arguably their most important application, the systems have recently caught the eye of healthcare professionals eager to sharpen their skills. For those in the healthcare field, virtual/mixed reality can provide training in procedures, techniques, and equipment use as well as simulate patient interactions in a far more immersive and realistic way.
According to the cone of learning from Edgar Dale, after two weeks, the human brain remembers 10% of what it reads, 20% of what it hears, and 90% of what it does or simulates. By this logic, virtual/mixed reality programs have the opportunity to completely revolutionize the way medical professionals are educated today. Education via simulation could be a productive step toward the system’s most adept and confident healthcare providers.
Virtual and mixed reality training programs provide future physicians/surgeons/emergency medical personnel the “hands-on” experience needed to be fully fluent the first day on the job. The simulations made possible by the technology are an excellent alternative to the traditional videos and textbooks used to educate. Educational videos and textbooks have been a useful way to disseminate information in the past, but in light of advanced technology, they seem a bit outdated. With this immersive style of learning, VR/MR training appeals to all types of learners: audio, visual, and kinesthetic.
Though not a replacement for physical hands-on practice, virtual and mixed reality are increasing situational experience and face time with “patients.” Albeit fictitious, the experience with patients provided by the simulations allows students to test the waters of caregiving. Virtual and mixed reality medical education is therefore useful for students who are not quite ready for the action that is the hospital. Giving students practice with the computer simulation is a low-risk alternative and, in extreme cases, can prevent patient harm.
Although in development for years, the concepts of virtual and mixed reality are transformative now due to a shift in consumer-grade technology and costs. With technology improving and prices falling, institutions will find it easier to engage the systems. To date, a number of pilot programs involving virtual and/or mixed reality training for medical students have been implemented worldwide. In 2016, the Cleveland Clinic began one such program for its medical students. In 2018, a well-known virtual reality company announced its partnerships with eight top U.S. medical residency programs to provide “hands-on” training opportunities for new surgeons. A recent report from an advanced technology higher education consortium revealed that as of June 2018, near 46% of universities and colleges have deployed VR in some form on campus. Though not exclusive to medicine, this statistic demonstrates the technology’s usefulness in classrooms nationwide. The technology’s new applications have many dubbing virtual and mixed reality, the new reality.
#7 Visor for Prehospital Stroke Diagnosis
When a patient has suffered a stroke, his or her outward symptoms often suggest the condition; weakness in the body, slurred speech, and confusion. From outward appearance, however, it is difficult say with confidence the cause and type of stroke a patient is experiencing.
Confirmation of stroke and identification of stroke type are the most crucial steps to intervention. And as timing of intervention is of the utmost importance, rapid diagnosis is essential. Once a patient has arrived at the hospital, medical staff is able to properly diagnose a stroke, and visualize the blocked artery (ischemic stroke), or the ruptured blood vessel (hemorrhagic stroke) causing trauma. However, a speedy trip to the hospital is not always ensured. To make use of the downtime that is the ride to the hospital, engineers have designed a visor for prehospital stroke diagnosis.
A noninvasive bioimpedance spectroscopy device that detects changes and distribution of cerebral fluids, the visor is able to detect brain pathologies like stroke, trauma, swelling, and others. When placed on a patient’s head, the visor emits low-energy frequency waves through the hemispheres of the brain. As the waves pass through the brain’s fluid, their frequencies change. The visor then assesses the changes in frequency between the two hemispheres. If the frequencies are markedly different, they indicate the occurrence of a stroke – the greater the difference, the greater the stroke’s severity.
Intended for use by emergency medical technicians, the visor is expected to be instrumental in providing hospital staff a more clear patient profile and speeding up time to treatment. Much like the portable ECGs used to triage patients in emergency situations, the visor is an efficient diagnostic tool. Diagnosis of a stroke with the visor in the field allows for immediate patient transport to comprehensive stroke centers with the ability to treat stroke – centers that are not always the first stop. In addition to ambulances, the visor also has applications in locations with high stroke probability (e.g. nursing homes) and settings where neuroimaging is not readily available (e.g. developing nations).
In studies, the visor has shown a 92% accuracy rate in identifying patients that have suffered a major stroke, while the accuracy rate of stroke diagnoses for emergency medical personnel using standard physical examination tools has been known to range anywhere from 40-89%. The device received FDA 510(k) clearance in January 2018 and is expected to be commercially distributed and used in the year 2019. The clearance includes a broad indication for use as an aid in the assessment of fluid volume differences between the cerebral hemispheres in patients undergoing neurologic assessment. The company is continuing clinical studies to further validate the device for identifying specific brain pathologies, including hemorrhage. With stoke they say “time is brain,” and implementation of the visor is poised to save both.
#8 Innovation in Robotic Surgery
Most surgeries performed today are the least time consuming and least invasive that science will allow. This innovation in surgical methodology saves patients and surgeons time and distress and is brought about by the integration of robotics.
Robots, computer programmable machines, are being used widely in society today. Portrayed by the media as high-tech malicious machines, robots have received a bad rap. In reality, robotic systems are fueling innovation in a peaceful manner.
Though popular for the automation of simple, repetitive tasks or those tasks harmful to humans, robots can be used to enhance certain human practices as well. Today, robots are increasing productivity and aiding in the conduction of several medical tasks. Popular in nearly all medical specialties, robotics is finding its niche in the operating room.
Advances in robotic surgery range from the development of more accurate planning tools and software, to increased automation of tasks during surgery. Specific examples of robotic surgical progress include the successful robotic planning and guidance of surgery on the spine, and the near automation of the process of bronchoscopy. In robotic spine surgery, robotic platforms are used for 3D surgical planning and intra-op guidance. Many platforms also include precision surgical arms designed for proper instrument positioning and implantation during surgery. The robotic assistance provided by these systems increases surgeon precision in rather challenging surgeries. The market for robotic spinal surgery systems has grown exponentially in the past four years. Several popular platforms are FDA approved, CE marked, and in operating rooms around the world.
Systems for robotic bronchoscopy are also becoming mainstream as they are automating the rather tedious and unpleasant process. Unlike traditional bronchoscopies, robotic bronchoscopy systems avoid incisions via insertion of flexible tubes through the body’s natural openings. The new concept of robotic bronchoscopy is increasing both accuracy and safety of the procedure while decreasing both invasiveness and cost. The world’s first robotic bronchoscopy platform received FDA clearance in 2016, but a new and improved platform was released and cleared in the spring of 2018. Integrating the latest advancements in robotics, software, and data science, the new robotic endoscopy platform utilizes a controller-like interface that physicians use to navigate the endoscope with improved reach, vision, and control.
Endovascular procedures are perhaps the newest field feeling the effects of robotization. Now able to be performed remotely, procedures like percutaneous coronary intervention (PCI) and peripheral vascular intervention (PVI) are lower risk for both the patient and surgeon. While the traditional approach to vascular intervention requires heavy lead protective equipment that impairs surgeon control, remote endovascular procedures via robotic platforms allow physicians greater control for improved outcomes. Though not yet fully integrated into practice, new robotic and telecommunication technologies are bringing remote vascular intervention closer to reality.
Minimally invasive robotic procedures are attractive to healthcare professionals as they offer significant cost savings in terms of pre- and post- operation care costs and length of stay at hospitals. But most importantly, the aforementioned advancements in robotic surgery qualify as an innovation as collective growth in the field yields significant improvements in patient outcomes and safety. Shortened recovery time and limited pain after surgery are just a few of the patient benefits seen with minimally invasive robotized surgery. Continued advancement in the space will only yield more precise and effective surgeries for patients requiring intervention in the coming year.
#9 Mitral and Tricuspid Valve Percutaneous Replacement
You feel its beat in your chest every day. It pounds while you bike up a steep hill, it pulses slowly as you drift to sleep at night, it flutters when you fall in love. The heart is one of the most vital organs. Responsible for supplying blood to the entirety of the body, your heart provides the oxygen and nutrients your cells need to survive. But the heart is prone to an array of problems – and we’re not talking about the dreaded broken heart. The heart can suffer from a variety of conditions affecting its muscle, valves, and/or rhythm. Many of its plaguing conditions may eventually require interventional cardiac surgery.
Historically, cardiac surgery has been known as complicated and dangerous. In its early years, surgery on the heart was extremely invasive, high risk, and yielded only minimal improvement in function. But the history of cardiac surgery has shaped its future, paving the way for innovation in the space.
Today, surgery on the heart is less invasive in nature and though still risky, is more routine and effective. Many cardiac procedures are now conducted percutaneously – via a catheter through the skin. A minimally invasive approach, percutaneous cardiac intervention is an effective alternative to cumbersome open heart surgery – especially for high risk patients. Percutaneous surgery has been game-changing in aortic valve intervention. Efficient for both valve repair and replacement, innovation in the percutaneous transcatheter surgery space has expanded to include replacements of the mitral and tricuspid valves.
The mitral valve controls blood flow from the left atrium to the left ventricle of the heart, allowing blood to flow in one direction through the heart and into the body. The tricuspid valve functions to prevent back flow of blood form the right ventricle into the right atrium to further ensure blood flow in one direction. When either of these valves are faulty, blood flow is compromised and the patient’s health is negatively affected. Unattended dysfunction in said valves can lead to severe consequences such as heart failure. Often valves are damaged past the point of repair and are required to be replaced.
Mitral valve insufficiencies that may require valve replacement surgery include mitral valve prolapse, regurgitation, or stenosis. To remedy these issues, a replacement valve stent is inserted in the percutaneous manner. Currently, several companies have stake in the mitral valve replacement market with a number of approved stent models being used in patients and a number of positive outcomes reported. Use of these devices has intensified in recent years and is expected to become increasingly mainstream due to their great success.
Though percutaneous procedures for the tricuspid valve are fewer and farther between, the technology in this space is novel and filling a void in the field of heart surgery. Performed for the first time in 2016, the world’s first implantation of a tricuspid valve stent under compassionate use protocols has shown excellent maintenance of valvular function and is expected to drive the demand for transcatheter tricuspid heart valve devices. The exploration of this technology in a greater patient population is ongoing, but with promising post-op results, the innovation has astounding implications for the future of cardiac care.
#10 RNA-Based Therapies
If you reflect back on your middle school science class, you might remember the concept of the central dogma. Used by geneticists for decades, the central dogma states that in the cells of the body, DNA is transcribed to RNA that is then translated into proteins. Proteins, the large molecules created from sequences of RNA, are responsible for many tasks in the body. Often associated with the body’s structure, functioning, or regulation, functional proteins are the key to healthy cells.
When proteins are damaged and non-functioning, health is compromised. It is these non-functioning or misfolded proteins that are the culprit in many genetic disorders. In new efforts to avoid misfolded proteins and remedy the genetic disorders plaguing members of our society, scientists are reflecting back to the dogma.
As the central intermediary in the expression of genetic information, RNA has become a popular target for therapeutics. Interfering with genetic data at the RNA level gives scientists the ability to intercept a patient’s genetic abnormality before it is translated into functioning (or nonfunctioning) proteins. Today, the most popular and successful mechanisms of RNA therapy include antisense nucleotides and RNA interference.
Antisense nucleotides are particles of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) that are complementary to a messenger RNA (mRNA) molecule – the RNA molecule that encodes a protein. Because these molecules are complementary to the given strand of mRNA, they bind to form a free double stranded molecule or double-stranded region of a chromosome. The then double-stranded region of the mRNA is unable to interact with ribosomes and, as a result, is unable to be translated into the protein of choice. Inhibiting the production of the protein encoded by the disease mutation mitigates the presence of the toxic proteins and the disorder.
Antisense nucleotide therapy is being explored in several conditions. To date, there are a few FDA approved antisense nucleotide therapies for the treatment of conditions such as AIDS-related retinitis and familial hypercholesterolemia. But innovative work in the space is focused on the treatment of the rare neurological disorder, Huntington’s disease. The goal of this strategy is to reduce the amount of abnormally large huntingtin (HTT) protein being produced in the cells of Huntington’s patients. Several nucleotide molecules are under clinical investigation in the form of phase I and II testing.
RNA interference is a natural regulatory mechanism in which RNA molecules inhibit gene expression by neutralizing targeted mRNA sequences. Andrew Fire and Craig Mello won the 2006 Nobel Prize in Physiology and Medicine for the discovery of this pathway. In RNA interference, one of two types of RNA molecules – either microRNA (miRNA) or short interfering RNA (siRNA) – is used to silence genes. MicroRNAs are short RNA molecules that bind to a part of the mRNA and trigger either the degradation process or sterically hinder protein production. Short interfering RNAs are a class of double-stranded RNA molecules functionally similar to microRNAs. Artificially, either of these molecules can be designed to target and suppress condition-specific defective genetic sequences. Known by other names such as co-suppression, post-transcriptional gene slicing, and quelling, RNA interference has shown immense potential.
RNA interference therapy is currently being explored for use in cancer and neurological diseases. Alzheimer’s disease is poised to be the most important application for RNA interference therapy if significant headway is made. The most successful RNA interference therapy to date, is for the treatment of hereditary transthyretin-mediated amyloidosis. Hereditary transthyretin-mediated amyloidosis is a genetic disease that causes buildup of abnormal amyloid protein in the peripheral nerves of the heart and body. In early 2018, the FDA accepted an NDA for this new therapy and granted priority review with a pending action date of August 2018. On August 10, 2018, the therapy received its anticipated approval and became the first FDA approved small interfering RNA interference therapy. The therapy also represents the first and only treatment for the incredibly rare, life-threatening disease.