A recent study found that prebiotic supplementation is an effective way of controlling appetite, yet still provides energy for children that are overweight or obese.
Obesity amongst children has shown to be a serious and increasing issue, especially in North America. Statistics show that one-third of children in the United States and Canada are obese or overweight. This is a major problem as adolescent obesity is an indication of adulthood obesity if not taken care of or reduced from an early age. Many treatments involve restrictive diets which can work for adults but are less effective in children, as they can reduce macronutrient intake, reduce children’s energy and in turn, promote weight gain through binge eating. Therefore, Hume et al. suggested that prebiotic supplementation may be an effective way to control appetite, stimulate satiety hormones (hormones that satisfy hunger) and energy intake of children that are overweight or obese. Prebiotics are derived from a special plant fiber that nourishes the good bacteria that is currently in the colon or large intestine. In comparison to probiotics that introduce good bacteria into the gut, prebiotics fertilize the good bacteria that is already there to help it grow, resulting in a better good-to- bad bacteria ratio.
To test this hypothesis, Hume et al. published a recent study in the American Journal of Clinical Nutrition (AJCN). The study was a randomized, double-blind, placebo-controlled trial. It consisted of 38 participants assigned to two groups. 20 were in the prebiotic group – 10 boys and 10 girls, and 18 in the placebo group – 7 girls and 11 boys. The participants were aged 7-12 years old, with a body mass index (BMI) of greater than or equal to an 85thpercentile during 2014-2015. One group was given 8 grams of oligofructose-enriched inulin (a prebiotic found in vegetables like artichoke) and the other group was given a placebo (maltodextrin) daily for 16 weeks. The dose of prebiotic and placebo were increased over a period of 2 weeks to allow for adaptation to the fiber and to minimize gastrointestinal symptoms. The primary outcome was the effect of prebiotics on appetite (serum satiety hormones, appetite ratings, and food intake) and the secondary outcome was the BMI z score. Since this study analyzed the effects of prebiotic supplementation independent of diet or exercise, participants were able to eat and drink what they chose; however, their diet was still recorded and analyzed through related software. Additionally, blood samples were collected at the end of the 16-week study to obtain serum for satiety hormone analysis.
The data showed a positive correlation of prebiotic supplements and weight control. In terms of energy, in the prebiotic group energy intake was reduced in comparison to the placebo group, where it was increased. However, the magnitude of energy intake between both groups was not significantly different. When appetite was analyzed, it was found that over the 16-week period, the prebiotic group reduced the amount of food that they usually consumed at the breakfast buffet. As well, prebiotic participants reported feeling significantly “more full” after their breakfast meal at the 16th week as opposed to the placebo group. Other significant results depicted that the prebiotic group had a reduced BMI z score of 3.4% compared to a 0.49% reduction for the placebo group.
Based on the results, prebiotics may help to improve appetite control in terms of pediatric obesity. The only limitation to this study was the use of parent-reported food records to measure energy intake, causing some inconsistencies in the data. Regardless, this study provides an important insight as there are limited studies related to the obese pediatric population, and can help to reduce the rates of both childhood and adult obesity, resulting in lower health issues.
The idea of mind-body association is too old to determine its origin. However, this idea has not been scientifically examined until researchers produced evidence for the association between emotional distress and cardiovascular disorders in the recent few decades. More importantly, there has been no such strong evidence in the context of cancer until a recent article with a focus on the association between psychological distress and cancer mortality was recently published.
The connection between mind and body was hypothesized centuries ago. However, research studies in this field are not so old. Studies in the recent decades have shown a relationship between psychological distress with symptoms of stress and anxiety, and risk of cardiovascular diseases, including heart attacks and stroke. There are also suggestions of a similar linkage between psychological distress and risk of cancer; prolonged emotional distress could not only suppress cellular defense mechanisms against tumor cells, such as suppressing the natural killer cell’s function, but also decrease immunological responses by the increased secretion of cortisol from adrenal glands. Although research findings support the direct association between distress and cancer, distress could indirectly increase the risk of cancer too; by the escalation of high-risk behaviors like smoking, sedentary lifestyle, bad diet, and weight gain.
In a new study, published in the British Medical Journal, researchers from England and Australia argued that the abovementioned observational studies failed to appropriately link their results to the different sites of cancer, discuss possible reverse causality and explore the alternative interpretations for their observed findings. So, the researchers designed their study to answer these knowledge gaps. They collected unpublished individual participant data from datasets of 16 community-based studies with similar tools to gather distress, cancer and background information. Using pooled raw data such as this is beneficial, as it provides an estimation of the associations more precisely than what usually happens in pooling the published results, as well as allowing the possibility of subgroup analysis and control of confounding variables. The datasets included vital status data of a total of about 200,000 persons of both genders, between 16 to 107 years old at baseline, who registered either to the Health Surveys of England (HSE) or Scottish Health Surveys (SHS) in 1994 and consented to answer to annual (HSE) or occasional (SHS) surveys until 2008. After excluding people with diagnosed cancer at the baseline, to ensure removing the possibility of reverse causality (anxiety and or depression secondary to being informed of cancer diagnosis), and the uncompleted data, a total of more than 163,000 individual’s data was entered into the statistical analysis process.
After statistical elimination of the effects of age and gender, the results of the study showed that there was about a 32% greater risk of cancer deaths among people with high levels of distress, compared to others who were minimally distressed. The researchers also reported a site-of-cancer specific analysis with statistical control over covariates such as obesity and adverse health behaviors, which indicated that there was a relatively unchanged association between distress and death of colorectal, prostate, pancreas and esophagus cancers, as well as leukemia. They suggested both direct and indirect mechanisms probably play roles in the observed association between distress and cancer mortality. The indirect mechanism would become evident in the behaviors of people with chronic distress; they engage in high-risk behaviors such as smoking, physical inactivity, and alcohol consumption more than those with lower levels or less frequent distress do. They also have a tendency to refuse health-seeking behaviors such as screening and/or treatment procedures. On the other hand, direct mechanisms may be related to the biological effects of distress. For example, the researchers mentioned that there are known immunological response changes that are related to depression.
In conclusion, the findings of this study add valuable evidence to the body of knowledge about the relationship between the mind and bodily responses. Further investigations, especially with methods that are designed to show causal effects of psychological factors on different health conditions, would provide the basis for change in clinical practice in the future.
Pharmacological treatment for heart failure with preserved ejection fraction is a complex process. Novel drugs have promising results.
Heart failure (HF) has been considered a common final pathway of many illnesses such as cardiovascular, metabolic, and kidney diseases. Heart failure can be further subcategorized depending on the level of the heart’s ejection fraction – the percentage of blood that leaves the heart during each contraction. The treatment of HF patients with reduced ejection fraction (HFrEF) has progressed, but not for HF patients with preserved ejection fraction (HFpEF). Currently, available trials regarding HFpEF are not able to provide definitive results for appropriate treatments.
American researchers from the Northwestern University Feinberg School of Medicine, therefore, analyzed large-scale multicenter HFpEF clinical trials and discussed the pharmacological efficacy of the available strategies for HFpEF. The pathophysiological mechanism of HFpEF is associated with a pro-inflammatory state that causes coronary microvascular endothelial dysfunction in the heart [e.g., reduced nitric oxide (NO), bioavailability, reduced cyclic GMP (cGMP)/protein kinase G (PKG) signaling, abnormalities in titin, and increased stiffness of cardiomyocytes] and, consequently, leads to HFpEF. A cascade of further events are triggered as a result of HFpEF, including increased left ventricle filling pressures, left atrial dysfunction, atrial fibrillation, pulmonary venous congestion, dyspnea, renal hypoperfusion and dysfunction, water retention, worsened pulmonary venous congestion, pulmonary hypertension, and right ventricular (RV) failure. A neurohormonal modulation is also observed and can explain the efficacy of neurohormonal antagonists as a pharmacological strategy.
Potential benefits may be observed with angiotensin converting enzyme inhibitors, which are widely used in many of the comorbidities commonly associated with HFpEF such as diabetes, hypertension, and chronic kidney disease. HF hospitalizations seem to be reduced using angiotensin-receptor blockers, especially in HF patients with a less severe HFpEF and with lower levels of natriuretic peptides (proteins that induce excessive sodium excretion through urine). A few available studies allow the conclusion that a less severe form of HFpEF and obesity-related HFpEF, as well as patients who are diagnosed with HF syndrome may benefit from mineralocorticoid receptor antagonists. Nitrates do not seem to contribute to the management of HFpEF. Digoxin is also not recommended in most cases of HFpEF, but may have positive effects in HFpEF patients with pulmonary hypertension. Beta-blockers are a very common medication for HFpEF patients; they seem to induce significant improvement in walking distance, but not in oxygen consumption. It is possible that phosphodiesterase type 5 inhibitors may be inefficient in most HFpEF patients, especially in those without severe left ventricular hypertrophy. Novel pharmacological agents that have been tested for the treatment of HFpEF include angiotensin receptor neprilysin inhibitor LCZ696, endothelin receptor antagonists (ERA), inorganic nitrate-nitrite substances, sodium-glucose cotransporter-2 inhibitors (SGLT-2), soluble guanylate cyclase (sGC) stimulators, and riociguat. The potential benefits of these new promising pharmacological strategies are being investigated.
It is unlikely that a single pharmacological agent will be able to provide benefits to every patient in a heterogeneous population living with HFpEF. However, it is possible that target therapies, such as those used in cancer patients, may be potentially efficient for HFpEF syndrome.
Short procedures may disadvantage bivalirudin (Angiomax) use during primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), according to a secondary analysis of HORIZONS-AMI pointing to early stent thrombosis risk.
When bivalirudin was used, rates of definite acute stent thrombosis within 24 hours were higher if PCI took less than 45 minutes from arrival at the catheterization laboratory to the final angiogram than if it the procedure was longer (2.1% versus 0.7%, RR 2.87, 95% CI 1.01-8.17). However, no difference by procedure duration was seen with heparin plus glycoprotein IIb/IIIa receptor inhibitor (GPI) use.
"Short-acting medications, such as bivalirudin, may not allow for adequate antithrombotic effect of oral antiplatelets in fast procedures," suggested Duane S. Pinto, MD, MPH, of Beth Israel Deaconess Medical Center in Boston, and colleagues in their reported appearing online in JAMA Cardiology. "The pharmacokinetics of bivalirudin and clopidogrel offer insight."
"When the primary PCI procedure is completed rapidly, adequate antiplatelet effect may not have been achieved with oral agents, particularly if gastrointestinal tract absorption has been slowed in STEMI. In this setting, the short half-life of bivalirudin (25 minutes) leaves the newly implanted stent relatively unprotected against acute stent thrombosis for short procedures," Pinto's group explained.
"Conversely, the duration of antithrombin effect is longer and rapid antiplatelet effect is achieved with heparin plus GPI."
The authors suggested that alternate strategies, such as a high-dose prolonged infusion, are warranted in order to preserve the survival and reduced bleeding benefits of bivalirudin while chipping away at the stent thrombosis problem.
Their present analysis of the HORIZONS-AMI randomized clinical trial included 3,602 STEMI patients who presented within 12 hours of symptom onset. Participants were randomized to bivalirudin or heparin plus GPI.
Shorter procedures were less complicated and tended to be performed in younger patients that were less likely to smoke or have high blood pressure.
Ohio's 2014 Medicaid expansion improved health and financial benefits for hundreds of thousands of low-income Ohioans, according to an assessment supported by RTI International.
The Ohio Medicaid Assessment found that the Medicaid expansion lowered the amount of uninsured individuals among low-income working adults to 14 percent, the lowest percentage ever reported.
"Our analysis found that the Medicaid expansion improved access to physical and mental health care for those who would be otherwise uninsured or undiagnosed," said Thomas Duffy, survey research scientist at RTI who assisted in the analysis. "This helps to not only improve the wellbeing of individuals, but reduce costly emergency room visits and the costs of controlling chronic health conditions."
Under the Affordable Care Act, Ohio and 30 other states expanded Medicaid coverage to those up to 138 percent of the poverty line, or $16,243 per year for an individual. Before the expansion, eligibility was limited to poor children, parents and disabled individuals.
To develop the Ohio Medicaid Assessment, RTI assisted in the data collection and analysis along with the Ohio State University College of Public Health, Ohio University, and Ohio Colleges of Medicine Government Resources Center at the request of the Ohio General Assembly. The project was funded by Ohio Medicaid.
Among more than 702,000 who received Medicaid coverage under the Ohio Medicaid expansion, the report found the following:
75 percent were uninsured previously 27 percent were diagnosed with at least one chronic condition after receiving coverage 32 percent were diagnosed with substance abuse or dependence 57 percent were unemployed Nearly a third were positively screened for depression and anxiety disorders To conduct the report, researchers analyzed a telephone survey of more than 7,500 Medicaid beneficiaries and collected data from medical records and biomarker specimen collections. RTI assisted with writing the statutory report and was the primary author of the methodological report.
Intrauterine insemination (IUI) is a technique of assisted conception in which washed and sorted motile sperm is inserted through the uterine cervix into the uterine cavity to increase the chances of natural fertilization of the oocyte within the fallopian tubes. It is indicated in severe or moderate male factor infertility and in mild unexplained infertility.
Its chances of success depend upon several factors. The live birth rate is lower than the pregnancy rate, and therefore the success rates published by various centers should be evaluated accordingly.
Prognostic factors
1. Cause of infertility
First of all, conception rates depend, though marginally, on the reasons for infertility. The duration of infertility also plays a role. Infertility due to anovulation or unexplained infertility is somewhat more easily treated with IUI than is endometriosis or male factor infertility.
2. Ovarian hyper stimulation
Whether or not medications are used to induce ovulation and the type of protocol used may have an effect on the success rates. The follicular response and increase in endometrial thickness following induction of ovulation may also act as prognostic markers, though not statistically significant. Many centers have reduced the dosage of drugs used to stimulate the ovaries because of the high risk of multiple pregnancies with these protocols. Superovulation does double or triple the pregnancy rates but also the number of multiple pregnancies. This can be as high as 20 percent for twins, and 40 percent for higher-order gestations. Ovarian hyperstimulation syndrome is also a foreseeable risk with increasing numbers of preovulatory follicles.
3. Age
The age of the woman undergoing the procedure significantly affects how well it works. Women who are below the age of 40 years, in general, have a more than 50 percent chance of achieving pregnancy after six cycles of IUI, with a success rate of over 75 percent after 12 cycles. Some other sources put the cumulative pregnancy rate at 20-33 percent with six cycles of ovarian hyperstimulation with IUI.
The importance of female age lies in the well-established reduction in oocyte quality as age increases, which is not offset by overcoming barriers to fertilization. IUI success rates start to decline even after the age of 35 years. For women above 40 years, live births may occur in only about 1.5 percent of women who have undergone IUI treatment cycles. For these reasons, this is a poor option for women older than 40 years, and even after the age of 35 it should be offered with extreme caution.
4. Semen parameters
Sperm count and sperm preparation techniques may make a difference in the ease of conception with IUI.
The use of fresh sperm has a higher conception rate than the use of frozen and thawed sperm. The sperm characteristics affect pregnancy rates, including the total motile fraction (TMF), the morphology and the motility of the washed sperms. The TMF significantly increases the pregnancy rate to almost double, when it is between 10 and 20 million, but its reduction to less than 10 million is associated with low success rates, and also a count above 20 million, though the reason for this latter finding is unknown. Even within this classification, a TMF of less than 1 million was linked to disappointing rates, while a TMF less than 5 million depends for its success mostly on the sperm morphology, ranging from less than 6 percent when abnormal sperms are abundant to almost 20 percent when normal morphology is present in most sperms.
5. Timing and number of inseminations
If the timing of ovulation is not correctly detected, the time of insemination may not be synchronized with the period of peak female fertility within the cycle. Thus the appropriate technique for working out whether ovulation has occurred or not needs to be used. A premature LH surge occurs in many cases, from a quarter to a third of treated women, which reduces the pregnancy rates. The use of LH antagonists or the use of clomiphene citrate to prevent an early surge is under study and may produce a significant rise in the success rates.
Number of inseminations within a cycle: If insemination is repeated twice within the same cycle, the number of pregnancies may go up.
6. Donor sperm
Successful insemination with donor sperm is again linked with the age of the woman, and has a 22 percent conception rate per cycle compared to less than 10 percent when only homologous sperm is used. Its use resulted in the following per cycle live birth rates:
Under 35 years - about 16 percent
35 to 39 years - 11 percent
40 to 42 years - less than 5 percent
43 to 44 years - just over 1 percent
Over 44 years - nil
However, higher rates have been reported in the US, with 10-15 percent live births in the 41-42 year age group, and 5 percent in women older than 42 years.
By Keynote ContributorDr. Richard ThompsonHead of Research, Findacure
Innovation is something of a buzz-word in modern medicine and rightly so. In order to deliver the best care and treatment to patients it is crucial that we are open to new ideas and encourage scientific advancement.
Finding new ways to successfully convert novel ideas into day-to-day practice is crucial to improve healthcare. However, all too often our focus on innovation is on new technologies, new scientific methods, or new drugs – it becomes a quest for the ‘next big thing’.
These are unquestionably important for treatments to be developed and reach patients; however, they are not the only form of innovation, and arguably not the form of innovation most needed in modern, cash-strapped healthcare systems.
Credit: Costello Medical Consultancy and Findacure
Innovation is also equally about innovative ideas – finding new ways to deliver a service or improved ways to use current resources. Drug repurposing is an excellent example of this form of innovation: using a scientific approach to identify new uses for existing drugs.
This type of research is clearly less ‘sexy’ than the development of novel treatments or advanced therapies like gene editing, as it does not produce an exciting new molecule or genetic construct. Subsequently people tend to believe that a repurposed therapy can never be truly novel or transformative, it just offers an incremental improvement.
Nothing could be further from the truth. The repurposing of one of the first monoclonal antibodies is a great example. It has been repurposed from cancer into multiple sclerosis, acting to effectively boost the immune system to protect against the disease’s degenerative effects. This is a novel mechanism to treat the condition derived from repurposing research: clearly a great form of innovation.
Credit: Costello Medical Consultancy and Findacure
The challenge of rare diseases
Drug repurposing has real promise for rare genetic conditions. There are over 7,000 different rare diseases and, with rapid advances in genomics, the number is constantly expanding. Unfortunately, only around 400 have licensed treatments, which leaves millions of people worldwide with little hope of disease-altering clinical support.
However, our ability to understand the underlying mechanisms of such unsolved diseases is also expanding with the rise of genomics. It is in these conditions that repurposing has its greatest potential.
Firstly, potential to deliver a meaningful and novel disease modifying treatment to a previously ‘unsolved’ disease, simply by matching drugs to impaired biochemical pathways. Secondly, repurposing offers a real chance to deliver this treatment relatively rapidly, and potentially inexpensively, to patients.
Credit: Costello Medical Consultancy and Findacure
How drug repurposing works
Drug repurposing works in two distinct phases: identification of candidate drugs and testing of their effect.
The identification of repurposing opportunities is a burgeoning field of innovation, which can span simple clinical serendipity, advanced text mining approaches, and analysis of gene expression patterns.
Traditionally, serendipity has been a major driver in drug repurposing. The treatment of leprosy is a classic example. With no viable treatment clinicians were simply left to manage the symptoms of this devastating condition. Patients often suffered from severe discomfort and pain, preventing sleep.
One of Israeli physician Jacob Sheskin’s patients suffered so severely from this, that he felt compelled to prescribe a drug originally marketed as a sedative, which was prescribed to pregnant mothers with disastrous consequences for the development of their children. This treatment not only helped the patient sleep, but began to have a rapid impact on the patient’s other symptoms. This drug is now used as an effective treatment for leprosy, its side effects well understood and managed.
This type of serendipitous repurposing makes for an excellent story, but a poor route to deliver a wide range of new treatments to patients. More often clinical-led innovation is based on an individual’s knowledge of disease progress or drug targets and side-effects. This type of expert driven repurposing has been the norm for years.
Recently however, things have begun to change. Firstly, drug screens have become increasingly prevalent, as a simple route to identify compounds with potential therapeutic effectives in a target disease.
In repurposing studies, prior knowledge about disease and drug mechanisms can also help to construct ‘intelligent’ screens, which specifically target a small set of drugs thought to act on the relevant pathway.
Beyond screening technologies, the wealth of data available in the digital age has spawned many new data analytic techniques that are helping to drive a more systematic approach to repurposing. Text mining approaches are allowing bioinformaticians to search the published scientific literature for connections between drugs and diseases.
In its simplest form, text mining identifies co-occurrences of drug and disease terms in the same sentence across hundreds of thousands of scientific articles. This allows a much more comprehensive review of published papers than can be managed by researchers alone.
Furthermore, new advances in natural language processing and machine learning allow computer algorithms to go beyond the sentence structure and infer connections between drugs and conditions that are not explicitly mentioned in the text. While such inferences still require extensive evaluation by human experts, they could provide a gateway to some truly novel repurposing opportunities.
Another exciting innovation is the field of transcriptomics – essentially the study of all of the genes that are active in the body’s cells. The genes that are active in a cell and the level to which they are used determines how a cell functions.
In genetic diseases, the expression of certain genes is likely to be very different to those of unaffected individuals. This produces a specific ‘transcriptomic signal’ for certain diseases in certain cells. Drugs can also alter the expression of genes in the body, as such they too can have a ‘transcriptomic signature’.
A new approach to repurposing is to attempt to identify the transcriptomic signals of specific drugs that are the opposite of the signals for a disease. In theory, this should allow the drug to cancel out the disease signal, normalizing the gene expression in affected cells, and eliminating the disease symptoms.
This type of approach is very new, but has great promise. The team at the Cambridge biotech Healx have recently used these methods to identify a potential repurposing candidate for the rare disease CDKL5.
Proof of concept
After a repurposing opportunity is identified, the second major component of a repurposing study is the proof of concept. This is the completion of rigorous preclinical and clinical trials to test the effect of the candidate drug in the patient population. While this follows the same basic rules used in any drug development process, repurposing does offer a few key advantages.
Firstly, repurposing uses compounds for which a large amount of detailed information is already known. Its absorption by the human body, its effect in its licensed condition, its side effects in diverse human population, its tolerability, and even its effect in a range of secondary conditions are all likely to be well known and documented.
This prior knowledge is the biggest advantage in repurposing. It not only helps to speed the identification of viable repurposing opportunities for a condition, it can also act to lower the need for early stage clinical trials which test drug absorption and tolerability in humans.
Removing such steps in the clinical pathway helps to reduce the time drugs take to reach clinic and spend on clinical development. This has the potential to lower development costs, which one would hope could lower the price of the drug on the market.
Credit: Findacure
Success rate of repurposing
A final key consideration with repurposing is success rate. Due to higher levels of knowledge about the candidate drug’s behavior in humans from the very start of the project, repurposing projects are much more likely to advance to clinic than novel drug discovery.
While the latter is estimated to have a success rate often in the single figure percentages, repurposing projects are estimated to be delivered successfully in about 30% of cases.
Indeed, the US based charity Cures Within Reach conducted a survey of the 200 research projects they had funded 1998-2009. They found that none of the 190 de novo projects had touched patient lives, but 4 of the 10 repurposing projects had delivered patient benefit, and subsequently switched all of their attention and funding to repurposing.
The future of drug repurposing
Due to the new innovations in identifying drug repurposing opportunities, the relatively low financial bar to enter the space, and the increased likelihood of repurposing success, it is a field of drug development that is open to groups beyond the pharmaceutical industry.
Biotechs, academics, and clinicians are all able to play a significant role, sourcing new ideas or developing them for the market.
More excitingly still, patient groups – charities, often rare disease focused, set up to promote the interests of a specific group of patients – are beginning to drive repurposing research forward. Such groups can act as funders for projects to identify repurposing opportunities for their condition, provide samples and expertise necessary for such projects, or help to plan and recruit for clinical trials.
While repurposing research is becoming more prevalent, it still struggles to receive the recognition or funding it deserves. It is for this reason that Findacure, Healx, and Cures Within Reach have come together to launch the Rare Repurposing Open Call.
This three-month project is a chance for the rare disease community to come together and share their repurposing ideas that are struggling to receive the funding and support they need to be fully tested and delivered to the patients that need them.
We all believe that repurposing offers real potential to rare disease patients, many of whom lack even the hope of treatment. By launching this call we hope to highlight the potential power of repurposing for this underserved group, and help to attract the funding and support they need to deliver real change.
About Dr. Rick Thompson
Dr. Rick Thompson joined the UK rare disease charityFindacure in 2015, after completing his PhD in Evolutionary Biology at the University of Cambridge. As Head of Research, he is responsible for all scientific projects, with the aim of developing a socially financed drug repurposing program – Findacure’s rare disease drug repurposing social impact bond (RDDR SIB).
Rick has designed and completed a proof of concept study to demonstrate the feasibility of the RDDR SIB to the NHS, investors, industry, and patient groups. He also works to encourage industry engagement with rare disease patient groups, promoting an open and collaborative approach to rare disease research.
What are spherical nucleic acids (SNAs)? What do they consist of and how do they differ from linear nucleic acids?
Spherical nucleic acids are structures that are made by taking a nanoparticle template and using chemistry to arrange short strands of DNA or RNA on the surface of those particles. The spherical core of the nanoparticle creates a spherical arrangement of DNA or RNA, similar to tiny little balls of nucleic acids.
Even though the sequences can be identical, the properties of spherical nucleic acids are very different from linear nucleic acids. For example, SNAs bind complementary DNA or RNA much more tightly than linear nucleic acids.
This means that in the context of detection and the use of SNAs as diagnostic probes, you can use a lower concentration of a nucleic acid target, for example, associated with a given disease. And so, these have become the basis for high sensitivity and also very high selectivity probes, in molecular diagnostic tools.
How can SNAs be used for the detection of infections?
There's a technology called the Verigene system that was commercialized by Nanosphere, a company I had started, which was then sold to Luminex. The Verigene system is used to sort signatures associated with disease, infectious disease in particular, and at very low concentrations, meaning at very early time points, to measure the presence of a particular infection. For example, in blood.
This is important because it can then be used, for example, to diagnose patients with sepsis, where being able to diagnose very early is really important because for every hour that a patient goes undiagnosed and untreated, the chance of mortality increases substantially.
Technology like this is changing the way molecular diagnostics is carried out. It is a very simple and rapid point-of-care medical diagnostic tool that allows for the detection of bacterial infections way before conventional tests. It is not necessary to go through the process of culturing the sample, which takes a long time and, therefore, increases patient risk.
So ultimately, you have a tool that is better for the patient because you get an accurate diagnosis earlier and better for the doctor, because the doctor is not needlessly prescribing a lot of unnecessary antibiotics, wasting money, and contributing to antibiotic resistance. Instead the tool can be used to figure out who has a bacterial infection and who doesn't; the appropriate treatment with effective measures then can be taken.
What does SNA synthesis involve?
In the case of developing a biological label, a gold nanoparticle is used for the template, and the SNA is made by bringing the template in contact with short strands of DNA that can be chemically anchored to it. In the case of gold, the anchoring groups are thiols.
We have developed a process that allows you to load the DNA or RNA on the surface of a particle to very high extents. The reason that's important is that it forces the orientation and gives the architecture both its spherical shape and also the properties that I've been mentioning.
Can you please outline your upcoming talk at Pittcon 2017 on ‘Nano-Enabled In Vitro and In Vivo Diagnostic Tools for Tracking and Treating Disease’? What bioassays will you be focusing on?
At Pittcon I will be focusing on two different types of bioassays:
Ones based upon the Verigene system
A new technology that allows one to measure intra-cellular nucleic acid targets -- mRNA
Both technologies are based on SNAs, which are structures that can enter a live cell, bind to a particular target, in this case an mRNA target, and elicit or liberate a fluorophore signaling entity that lights up the cell.
This allows you to then measure for the first time, the genetic content of live cells. In addition to measuring the genetic content, cells can be differentiated based on mRNA expression levels. The location of the RNA within the cell can also be measured, which is especially exciting because nobody has ever been able to do that in live cells before now.
This is especially interesting because when coupled with a technology like flow cytometry, you are able to sort cells based upon genetic differences. Millipore is a company that has commercialized this technology and produced many variations of these types of architectures, so that researchers can begin to look, for example, for rare cell populations and pick out circulating tumor cells, in the presence of healthy cells.
This becomes a way of studying the cells and the number of them. It also allows you to isolate them so that you can study them after the fact. You can pull them away from majority cell populations, culture them, and use them to understand the origins of genetic differences. For example, looking at how a cancer patient’s cells respond to different types of therapeutics.
This is a major step towards personalized medicine and increasing our capabilities with respect to probing cellular systems. It's also potentially useful for high throughput drug screening, where you can look at how different types of drug molecule activate or suppress different types of genes. You can get a visual readout in this case, based upon the use of this technology, we refer to as nano-flare technology. Millipore has commercialized a form of nanoflares they refer to as smart-flares.
What will be the focus of your second talk at Pittcon 2017, ‘Spherical Nucleic Acids as Potent Immunomodulation Agents for Cancer Therapy’?
SNA structures also represent the basis for an entire new class of nucleic acid therapeutics. There are three central arteries of drug development:
Small molecules
Benefits are well known, aspirin being a great example.
Biologics
Seven of the top ten drugs are based upon biologics; these are antibodies, protein-based architectures. They have a lot of advantages and capabilities that go beyond what small molecules offer.
Nucleic acid medicines
Here short snippets of DNA or RNA are used to treat disease and attack it at its genetic roots.
Antisense drugs are based upon DNA and are used to soak up mRNA in cells and stop translation of that RNA and production of proteins that we associate with disease. The idea behind antisense is that you can regulate a person’s cells and convert an unhealthy cell into a healthy cell by knocking down the production of a specific type of protein.
Then came along siRNA technology – a similar concept in the sense that you're knocking down the production of specific types of proteins, but via different pathways. The idea of developing genetic medicine is really the concept of a type of digital medicine, where instead of every time you need a new drug you don't look for a new small molecule, you change the sequence of DNA or RNA being used based upon an understanding of biological pathways.
From a conceptual standpoint, these were really powerful technologies. They led to the development of many commercial approaches but have had limited success. The reason being, to truly realize digital medicine you need multiple things in play. One is you have to be able to synthesize DNA and RNA, and two, you have to be able to understand pathways.
These two issues have now been overcome; we know how to synthesize DNA and RNA, and thanks to the human genome project, we also know a lot about the pathways of disease and how to attack different types of pathways to treat disease. But the third, and perhaps most important requirement, is the ability to get the DNA or RNA to the site that matters. And that's where most attempts have fallen short.
This is where spherical nucleic acids are very important. SNA structures, which have no natural equivalent, can interact with natural systems completely differently from the native DNA and RNA from which they're derived. Almost every cell type in your body, other than mature red blood cells, recognize SNAs and rapidly internalize them without the need for transfection agents.
This is particularly interesting because, for example, putting normal DNA or RNA in creams and putting them on your skin won't make them go into your skin cells; but with spherical nucleic acids they'll rapidly take them up. This discovery therefore opens up the ability to create topical medicines, local medicines, that allow you to treat a lot of diseases.
And so we've been looking at this capability in terms of developing new types of treatments for skin disease. There are over 200 diseases with a known genetic basis. One can begin to think about creating therapeutics for the eye, ear, lung, bladder, and colon via similar approaches.
The fundamental properties of SNAs make nucleic acids relevant for treating a wide range of medical conditions not addressable with conventional nucleic acids. The first SNA constructs are in human trials for treating psoriasis.
How could SNAs be used in cancer vaccines?
Another application we've been researching is the use of structures as potent regulators of the immune system. SNAs will enter immune cells, dendritic cells, and if the sequence is correct, they will activate toll-like receptors, so that you can take an animal, or a patient in principle, and selectively activate their immune system.
This allows for the creation of new forms of vaccines, for example, where you can train a person’s body to fight a specific type of cancer. This is what is happening right now, we have a whole series of drug candidates based upon this approach, and I will be talking primarily about prostate cancer at Pittcon.
In principle vaccines like this could be developed to treat many different types of cancers, including cancer of the brain, bladder, colon, and melanoma.
What stage of development are SNA cancer vaccines currently at and what hurdles still need to be overcome?
The cancer vaccine work is just about to go into human clinical trials this year. The technology has been extensively vetted in animals and proven to be safe, for example, in primates.
The human trials are extremely important. With a cancer vaccine, you are modulating a person's immune system and there is a risk of creating autoimmune responses.
What are the next steps in your research?
For me, it's all about understanding what makes these structures so special and continuing to understand how we can build different forms of spherical nucleic acids, and use the unique properties of them to solve major problems in medicine and other areas of research.
Do we currently know why the spherical nucleic acids are internalized or is further research needed to fully understand this?
At the moment, we believe that they are recognized by what are called scavenger receptors; these are structures common to many cell types, and they're used to move cargo in and out of cells.
They have also been shown to recognize and bind to spherical nucleic acids much more tightly than linear nucleic acids, and so effectively we have, in part by accident, discovered and designed an architecture that is recognized by natural biological machinery, scavenger receptors that lead to their internalization into a cell.
There are several papers that explore this for different cells types, and all of our research thus far is consistent with that conclusion.
What are you looking forward to at Pittcon 2017?
It's honestly a really exciting venue for anybody interested in analytical chemistry, new instrumentation, or new techniques associated with that instrumentation, and so, I particularly enjoy the frontier talks. But of course, I also enjoy the expo hall and seeing all the new technology on display.
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