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Spherical nucleic acids, or SNAs, are 3-D nanostructures consisting of densely functionalized nucleic acids covalently attached to the surfaces of spherical nanoparticle cores. Photo: Northwestern University

Now more than ever, multi-disciplinary collaborations are fueling the production of large-scale biological projects and research initiatives. These studies, coupled with innovative lab instruments, are providing unprecedented glimpses into the inner workings of the human body.

The results have boosted our understanding of how some of the world’s most difficult-to-treat diseases affect individuals, and have sparked a wave of new, innovative therapies to treat them.

At this year’s Pittcon Conference & Expo, held in Orlando from Feb. 27 to March 1, thousands of scientists from a variety of scientific disciplines gathered to view the latest analytical techniques and state-of-the-art laboratory instruments that are fueling research—opening new avenues of scientific exploration that were previously not available.

The show floor featured more than 700 exhibitors representing over 30 countries. The conference also included a packed agenda of informative lectures and presentations from some of the minds behind the latest research.

A new wave of therapeutics
For the last 50 years, the majority of top-selling pharmaceuticals on the market were small molecules. But as of 2016, eight of the top 10 drugs were biologics. The transition to biologics demonstrates the high potential to treat diseases that small molecules cannot.

But according to Chad Mirkin, director of the International Institute for Nanotechnology and the George B. Rathmann Professor of Chemistry at Northwestern University, the next wave will highlight nucleic acid medicines, which could allow clinicians to attack a specific disease at its genetic roots.

Mirkin presented his group’s latest developments in using spherical nucleic acids as therapeutic agents against a variety of diseases at Pittcon.

Spherical nucleic acids, or SNAs, are three-dimensional nanostructures, typically consisting of densely functionalized and highly oriented nucleic acids covalently attached to the surfaces of spherical nanoparticle cores.

Mirkin invented SNAs at Northwestern in 1996, but is just now revealing their true potential as versatile tools in medicine.

As Mirkin explained during his presentation, SNAs are produced by taking a nanoparticle template and using chemistry to arrange short strands of DNA or RNA on the surface of the particles. The spherical core creates an arrangement of the DNA or RNA that is similar to tiny balls of nucleic acids. But the SNAs bind much tighter than linear nucleic acids.

The unique properties of SNAs offer distinct advantages compared to their linear counterparts. Prior research by Mirkin’s group showed that linear nucleic acids are unable to enter a patient’s cells. But when SNAs were tested in more than 60 different cell lines, all of the cell types safely internalized the SNAs without the need for a secondary agent, which can result in toxicity issues.

So, what if spherical nucleic acids could be delivered directly and locally into the body? For example, SNA-based creams could treat skin diseases or drops could be made for eye diseases. Additionally, injections could train local immune cells to trigger a system-wide response to treat autoimmune diseases. This is the vision of Mirkin and his group at Northwestern.

Current work with nucleic acid-based therapies primarily target liver diseases because when injected, the nucleic acids gravitate toward and accumulate in the liver. But Mirkin refers to liver diseases targets as “low-hanging fruit” and is working toward using nucleic acid therapeutics for a wider variety of afflictions.

There are more than 200 diseases with a known genetic basis, so the potential to use SNAs as therapeutic agents is large, and something conventional nucleic acids have not been successful with thus far.

During his presentation, Mirkin addressed the three requirements needed to make nucleic acid medicines a reality. The first, and rather obvious requirement, is the ability to make nucleic acids. This has been proven, as companies are making large quantities already.

The second is having a detailed understanding of biological pathways, which again is something researchers currently have a good grasp on, and are learning more every day.

The third, and most critical according to Mirkin, is delivering the medicines to the cells and tissues of interest. If this cannot be solved, then the other two requirements are irrelevant.

“If we can get nucleic acids to be taken up by these types of tissues rapidly, and we can get them to go into the appropriate cells, we can begin to think about treating disease that cannot be addressed currently with conventional nucleic acid proteins,” Mirkin said.

Mirkin and his team have found that the production of SNAs can resolve the third requirement—something he considers a “game changer.”

Reversing psoriasis
Psoriasis is a common autoimmune condition, with more than 3 million new cases in the U.S. each year. Current treatments can offer relief from symptoms for some patients, but the typically lifelong condition still does not have an effective cure. The condition causes a patient’s body to create an excess of a typically healthy protein, TNF-α. As a result, the immune system attacks the protein, leading to the formation of red patches and scales that can be itchy and painful for the sufferer.

The Northwestern group has already conducted both animal tests and human clinical trials using a gel made of SNAs that is able to reduce the amount of TNF-α protein produced, and therefore alleviate symptoms.

The results from animal models were encouraging, and proved that the effects of the condition could be reversed, opening up the potential for a psoriasis cure. Human clinical trials were initiated in 2016, and showed similar success as the animal trials. The trial demonstrated that the therapy is safe in humans, and showed a dose-dependent response. The next step is identifying the most effective dose for patients, and then expanding its use for other skin conditions.

Chad Mirkin
Director of the International Institute for Nanotechnology.

 

Entering the blood-brain barrier
Another exciting discovery Mirkin revealed during his presentation was success in getting SNA structures to pass through the blood-brain barrier to potentially help treat brain tumors.

The job of the blood-brain barrier is to shield the brain from any potentially diseased blood—making it nearly impenetrable. This presents a rather difficult challenge when trying to develop treatments for neurological diseases and brain cancers.

Mirkin has entered into a collaboration with Alexander Stegh, a member of the Robert H. Lurie Compressive Cancer Center of Northwestern University, to test the efficacy of SNAs against glioblastoma multiforme (GBM)—the most common and aggressive form of brain cancer, which does not currently have a cure.

After again seeing success in mouse models, Mirkin and Stegh initiated a Phase 0 human clinical trial at the Lurie Cancer Center in late 2017. While the trial is still ongoing, Mirkin noted that early results are promising.

The six patients involved in the study have had regrowth of their tumors and are candidates for tumor removal. Each patient received an injected dose of a drug currently known as NU-0129, which consists of RNA snippets arranged on the surface of spherical gold nanoparticles, prior to surgery. The gold nanoparticle core is only 13 nanometers in diameter.

When the drug is injected into the patients, it travels across the blood-brain barrier and enters the tumor, where it alters the genetic makeup of cancer cells to prevent them from multiplying and growing.

Once the tumors were surgically removed, the researchers used mass spectrometry to show that the SNAs did actually accumulate in the tumors. The team hopes further studies will prove that the accumulation will produce a therapeutic effect and could one day lead to a cure.

Mirkin’s ongoing work shows that this class of medicines can provide a privileged access to cells and tissues that conventional methods do not currently offer. Mikrin noted that these findings also create a pathway to develop new types of drugs rapidly and at reduced cost.

Mirkin was the recipient of the Ralph N. Adams Award at Pittcon 2018, which honors an outstanding scientist who has advanced the field of bioanalytical chemistry through research, innovation and/or education. This recognition is the latest of more than 130 national and international awards he has earned for his work over the years.

The missing link between genetics, environment
While Mirkin’s research approach focuses on tackling the genetic side of diseases, other teams are trying to better understand how the dynamic interactions between our genes, environment, microbiomes and overall lifestyle choices influence our chances of developing disease.

Jeremy Nicholson, director of the MRC-NIHR National Phenome Centre at Imperial College London, views this interaction, known as the field of phenomics, as the future of medicine.

A person’s genes only tell part of the story as to why some individuals develop a specific disease while others do not. Nicholson’s recent work focuses on biomarker identification as a way to learn about previously unknown aspects of diseases. To do this, Nicholson uses a combination of mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy.

Nicholson refers to his work as “analytical chemistry with a purpose.”

As he explained during a press conference at Pittcon, mass spectrometry has proven to be incredibly useful in gaining insight into protein structure, function and modification. But NMR can offer benefits that work around some of the limitations of mass spectrometry.

Together, these techniques can beat out conventional diagnostics, and offer an opportunity to track a patient’s entire journey—from the initial diagnostic phase through to the treatment phase and ultimate outcome.

“We run NMR spectroscopy on everything first. Apart from it being very useful diagnostically, it’s a fantastic tool for picking out bad samples, which really screw up mass spectrometry. So if you have a bad NMR sample, we pull it out. Something like two to three percent of all samples are contaminated and can make mass spectrometry very inefficient,” explained Nicholson. “You put NMR on the front end, it’s powerful enough analytically on its own to go around that sample. In the next few years, I think NMR will give mass spectrometry a run for its money.”

Nicholson and colleagues at Imperial College London have been long-time partners with teams at Bruker Corp., the only company to have both NMR and MS in its portfolio.

Bruker has helped accelerate Nicholson’s research by developing new technologies for high-throughput metabolic analysis, and the company revealed some of its latest additions at Pittcon.

Bruker’s timsTOF Pro ultra-high resolution quadruple time of flight mass spectrometer for high sensitivity proteomics can now be integrated with the Evosep One separation device for high-throughput clinical proteomics. The combination of the two instruments ensures high-level sensitivity, and for large sample cohorts, this enables biomarker research and validation on more than 200 samples per day—which Frank Laukien, president and CEO of Bruker Corp., considers a “breakthrough” for future clinical proteomics.  

Additionally, the IVDr-by-NMR solution from Bruker now offers biobanking applications to assess sample quality with rigorous SOPs. This can speed up translation to future diagnostic methods, whether for personalized medicine or population-wide studies on phenotypes and associated risk factors. The platform can provide quantitative data on 15 metabolic biomarkers in urine in a single experiment under full automation.

The instruments put “world-class biomarker discovery and validation capabilities in the hands of clinical researchers,” according to Gary Kruppa, vice president for proteomics at Bruker Daltonics.

Harmonizing data
Nicholson has been involved in metabolic phenotyping and metabolic profiling for more than 30 years. In collaboration with others at Imperial College London, he has used this expertise to initiate the International Phenome Centre Network (IPCN).

The IPCN is a research consortium with the goal of improving disease prevention, detection and treatment through “research harmonization.”

“This approach advances precision medicine by going beyond genetics to examine a broader array of factors that impact health,” explains the Centre’s website.

The main goal is to create global atlases of human disease and population health to enhance scientific and clinical understanding in unprecedented detail. It consists of more than a dozen international partners in Australia, Canada, the U.S., China and elsewhere.

“Together, we can tackle the genomic and phenomic areas of these diseases,” said Nicholson.

Thanks to the international collaboration, data from researchers doesn’t have to remain in specific institutions’ silos. According to the Centre, up to 85 percent of research is wasted because of poor study design and inaccessible study results. But the IPCN’s vast capabilities now allow research and study results to be shared across the globe—which not only enables more complex studies to be done, but also at lower cost and within quicker timeframes.

“The output of the Centre is astronomical,” said Nicholson, citing that the IPCN can run 15 to 20 studies at one time, and produce up to 2 tetabytes of data per year.
Accomplishments of the Centre could improve treatments and outcomes for hard-hitting health concerns such as cancers, autism, obesity, type 2 diabetes and mental health conditions.

Using robust and harmonized data sets representing the world’s diverse populations, this research will inform global public health policies and the development of new therapies.

“We want to take discoveries from the population about disease risk and then re-apply it at the individual level,” said Nicholson.

Researchers working at the International Phenome Centre Network. Photo: Imperial College London
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