Protein profiling reveals immune system dysfunction in Down syndrome

An article published online in Scientific Reports shows that Down syndrome may be a form of chronic immune disorder. In the largest and most comprehensive study of its kind to date, investigators at the Crnic Institute for Down Syndrome, the Sie Center for Down Syndrome, the University of Colorado, and Somalogic measured the levels of over 3500 proteins in the blood of Down syndrome patients and compared them to non-Down syndrome controls. Their results provide a new framework for understanding the physiological mechanisms that drive the altered disease susceptibilities seen in individuals with Down syndrome, and suggest that individuals with Down syndrome could benefit from therapies that decrease or modulate immune responses.

Down syndrome, or Trisomy 21, is caused by having three copies of chromosome 21 instead of two. Although the genetics of Down syndrome have been known for 60 years, it is still unclear how having the extra chromosome leads to various Down syndrome traits, including changes in common disease susceptibilities (e.g., Down syndrome individuals are more likely to develop Alzheimer’s, leukemia and autoimmune disorders, but less likely to develop solid tumors and cardiovascular disease). Understanding the biology that underlies these differences could inform a wide range of medical conditions that affect not only Down syndrome individuals, but the entire population.

The researchers used the SOMAscan assay to compare levels of blood proteins in 165 individuals with Down syndrome and 98 controls, and they identified 299 proteins that differed significantly between the two groups. Surprisingly, most of these proteins are not encoded by genes located on chromosome 21, but are associated with immune system control. Down syndrome individuals appear to have something that resembles an autoinflammatory condition, with elevated levels of proteins that promote inflammation but deficiencies in proteins that help eliminate foreign pathogens. The findings provide a new way to think about Down syndrome and possible targets of therapies to improve the health and lifespan of those with Down syndrome as well as the general population.

Sullivan, KD et al. (2017) “Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation” Scientific Reports 7(1): 14818.

 

Modified DNA aptamer inhibits IL-1α signaling

Modified DNA aptamer inhibits IL-1α signaling

In an article published online in Nature Communications, scientists from SomaLogic and Yale University report that they have successfully generated a novel Slow Off-rate Modified Aptamer (SOMAmer) molecule that binds tightly to interleukin 1 alpha (IL-1α), an essential inflammatory protein implicated in cancer and other diseases. The SOMAmer (called SL1067) shows high specificity for IL-1α and can block its activity. SL1067 could therefore be a useful tool for elucidating IL-1α’s role in producing inflammation and regulating the immune system.

IL-1α/SL1067 structure with IL-1α in green. SL1067 is in cyan with naphthyl-modified residues in orange.

The researchers determined the three-dimensional structure of SL1067 bound to IL-1α, providing the first high-resolution structure of this essential protein. This is also the first crystal structure of a SOMAmer that contains bases modified with naphthyl groups, five of which are involved in IL-1α binding. The naphthyl modifications allow SL1067 to adopt a very compact structure with unusual three-dimensional shapes that have never been seen before. Since SL1067 is small (only 22 nucleotides in length), stable and easily synthesized, it serves as an excellent starting point for development of novel therapeutic molecules that target IL-1α.

 

Ren, X et al. (2017) “Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling” Nat Commun, epub ahead of print.
https://www.nature.com/articles/s41467-017-00864-2

Protein changes may signal side effects in drug trials

Protein changes in blood can provide early warning of potential harmful side effects from experimental drug candidates

In an article published “early online” in the American Heart Association journal Circulation, researchers at Pfizer, the Karolinska Institute, the University of California, San Francisco and SomaLogic describe how the measurement of blood-based protein changes in response to treatment with an experimental drug candidate may improve the efficiency and safety of clinical drug development. The published study used a nine-protein-based risk score to detect potential cardiovascular problems with a drug candidate (torcetrapib) well before significant adverse symptoms manifested themselves in patients in the drug’s clinical trial. Their analysis also identified changes in approximately 200 additional proteins that help describe the biology behind those adverse symptoms, which is applicable more broadly in cardiovascular disease management.

Pfizer’s phase three clinical trial (named “ILLUMINATE”) of torcetrapib, a drug candidate that had been shown to raise levels of “good” cholesterol and lower levels of “bad” cholesterol, was expected to confirm its blockbuster potential in reducing the risk of serious cardiovascular events such as heart failure and stroke. Instead, ILLUMINATE was halted abruptly in 2006 due to an unexpected increase in deaths and cardiovascular problems in trial subjects receiving the new drug candidate. At the time the trial was halted, Pfizer had invested 15 years and nearly a billion dollars in developing torcetrapib.

The Circulation study describes an attempt to determine if the problems from torcetrapib treatment could have been detected earlier, and thus at a lower cost. In this study, the researchers used the SOMAscan® assay to measure changes in the levels of over 1,000 proteins in blood samples from ILLUMINATE trial participants. Using a previously validated, nine-protein cardiovascular risk score, they found that they could successfully predict the harmful effects of torcetrapib in specific patients after only three months of treatment—much earlier than the point at which the ILLUMINATE trial was terminated (18 months).

In addition, a wider analysis of approximately 200 blood proteins that significantly changed in torcetrapib-treated patients revealed that the drug candidate had widespread, unexpected effects on normal immune and inflammatory processes. In addition, changes in only eight of the proteins measured were sufficient to explain the biology underlying the hypertension side effect seen in clinical trials. Beyond torcetrapib, these insights can also provide additional guidance for more personalized and targeted prescribing of currently marketed cardiovascular drugs, such as statins and ACE inhibitors.

Torcetrapib is just one member of a promising class of cardiovascular disease-prevention drugs, cholesteryl ester transferase (CETP) inhibitors, that have garnered considerable interest from the pharmaceutical industry. In addition to Pfizer, both Eli Lilly and Roche had candidate CETP inhibitors that were dropped late in development due to lack of efficacy. However, Merck recently announced that their drug candidate anacetrapib successfully completed the longest CETP clinical trial to date.

Expanding the work described in the Circulation paper to include comparative analyses from all of these drug candidate trials from different companies could provide, not only enhanced understanding of critical protein changes related to side effects, but could also reveal early signs of “positive” protein changes that would help accelerate the successful development of more promising candidates from not only this drug, but across many different classes and even disease types.

Reference: Williams, SA et al. (2017) “Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib” Circulation (published early online October 3, 2017).

Contact:
Fintan R. Steele, Ph.D.
Chief Communications Officer
T: 720-214-3080
C: 617-816-9834
fsteele@somalogic.com

About SomaLogic
SomaLogic is committed to helping people worldwide receive timely, accurate, trustworthy and actionable information that helps them manage their personal health and wellness. To realize this vision, we are creating and delivering the ”SOMAscan Platform,” a clinically useful and affordable health information system based on comprehensive and personalized protein measurement, delivered broadly through a global ecosystem of partners and users.

 

 

Reynolds appointed CEO of SomaLogic

Reynolds appointed CEO of SomaLogic

Former CEO Byron Hewett steps down after successfully building the foundation for SomaLogic’s future growth

Boulder CO – April 5, 2017 – SomaLogic announced today that Board of Directors member Alister W. (Al) Reynolds has agreed to become the next company Chief Executive Officer.  He is replacing Byron Hewett, who elected to step down from the role following several years of successfully leading the company through its initial growth into a successful commercial entity.

Alister (Al) Reynolds

Alister (Al) Reynolds (Photo by Glenn J. Asakawa)

The announcement was made by SomaLogic Founder and Board Chairman Larry Gold, who praised both Hewett’s leadership over the past several years, as well as the uniquely relevant experience that Reynolds now brings to the role. “As we now enter a new phase in our development we are absolutely delighted that Al, with his deep knowledge of SomaLogic and his broad experience in healthcare, is available and willing to step into top-level leadership at this critical time,” said Gold.

Reynolds, who has served on the SomaLogic Board since 2003, said that he is both excited about taking on this new role and eager to get started. “I don’t think the potential impact of SomaLogic on the quality of life of so many people around the world can be overstated,” said Reynolds. “I have been fortunate to be a contributor to the company’s progress to date, and I look forward to serving this ground-breaking company in new ways going forward.”

In addition to his Board position at SomaLogic, Reynolds currently serves on the Board of Prodigo Solutions Inc. Previously, he served in a variety of senior executive positions for Quest Diagnostics Inc. and its predecessor company Corning Inc. for over 20 years, culminating in responsibility for the nationwide operations of Quest Diagnostics. For the past 14 years Reynolds has served on the Boards and been a private investor in several successful early-phase companies, primarily in healthcare. Reynolds holds a bachelor’s degree in economics from Colgate University and an MBA in finance from Cornell University.

“I am very proud of what the SomaLogic team has accomplished these past several years,” said Hewett, “particularly the initiation and growth of an outstanding commercial program that matches the unequalled research program already here when I arrived, and the intensive strategic planning we have done to successfully build the foundation for the company’s future growth.” Hewett cites the strategic plan as the main reason for his decision: “The different kind of leadership expertise it requires to fully achieve this strategy led me to the decision that now is the right time to hand off the baton to a new CEO.”

Hewett will stay on as an advisor to SomaLogic, and will work with the Board and Reynolds through the transition and beyond. “Byron has been a valued colleague and leader in helping SomaLogic develop a needed commercial focus,” said Gold. “We are grateful to Byron not only for his contributions to date, but also for his willingness to help and support SomaLogic in the future.”

Contact:
Fintan R. Steele, Ph.D.
Chief Communications Officer
T: 720-214-3080
C: 617-816-9834
fsteele@somalogic.com

About SomaLogic
SomaLogic is committed to helping people worldwide receive timely, accurate, trustworthy and actionable information that helps them manage their personal health and wellness. To realize this vision, we are creating and delivering the ”SOMAscan Platform,” a clinically useful and affordable health information system based on comprehensive and personalized protein measurement, delivered broadly through a global ecosystem of partners and users.

 

Modified DNA aptamers: Two is better than one

Modified DNA aptamers: Two is better than one

In a study published online on March 6, 2017 in the Proceedings of the National Academy of Sciences (PNAS), SomaLogic scientists report on the generation and characterization of a new class of SOMAmer that contains two different types of modified nucleotides. Current SOMAmer® reagents contain deoxyuridine (dU) bases with protein-like modifications at the 5-position, which increases the chemical diversity of SOMAmer libraries and expands the number and type of protein targets that can be bound. Now, for the first time, researchers have created new SOMAmer libraries that contain an additional base: a 5-position modified deoxycytosine (dC).

The researchers synthesized a total of 18 different SOMAmer libraries that contained zero, one or both types of modified bases. To test the libraries, they selected new SOMAmers against the known human therapeutic target protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), a critical protein in heart health. They found that the SOMAmers with the best binding to PCSK9 contained both types of modified bases. Similar results were observed with another target protein, prostate-specific membrane antigen (PSMA), a predictor for progression and prognosis of prostate cancer.

SomaLogic researchers are now incorporating these new SOMAmer reagents in ongoing studies across a wide range of biomedical science, from basic research to therapeutic applications.

Reference: Gawande et al. (2017) Selection of DNA aptamers with two modified bases Proceedings of the National Academy of Sciences, published ahead of print March 6, 2017, doi:10.1073/pnas.1615475114

 

SomaLogic announces that it has joined the iCarbonX Digital Life Alliance

SomaLogic announces that it has joined the iCarbonX Digital Life Alliance

Agreement includes development of a China-based joint venture and an equity investment by the iCarbonX ecosystem in SomaLogic

BOULDER, Colo. – January 5, 2017 – SomaLogic announced today that it has agreed to join the “Digital Life Alliance” established by iCarbonX, the China-based company founded in 2015 to build a “Global Digital Health Ecosystem that can define each person’s ‘digital life’ based on a combination of individual’s biological, behavioral and psychological data, the Internet and artificial intelligence.” Under the agreement between the companies, SomaLogic will provide proteomics data and applications expertise to the Alliance to accelerate the ecosystem’s development. Also under the agreement, iCarbonX and SomaLogic will establish a joint venture in China to provide the SOMAscan® proteomics assay for research and health applications in China. The iCarbonX ecosystem will also make an equity investment in SomaLogic to help accelerate these efforts.

“We founded iCarbonX with the goal of hastening the day when each person can receive truly useful digital health information, derived from many different aspects of their physical being, that they can use to live a healthier—and thus happier and fuller—life,” said Jun Wang, Founder and CEO of iCarbonX. “Our new SomaLogic colleagues share that vision deeply, and they provide the world-leading expertise in proteomics that we need to realize that vision sooner.”

SomaLogic’s proprietary technology, built over 15 years of intensive developmental work, is now empowering researchers across academia and business to measure human proteins as easily as nucleic acids. “Proteomics will provide us with essential digital knowledge for helping to understand each individual’s constantly changing health status,” said Wang, “and SomaLogic’s technology uniquely provides the breadth and depth of protein-based information we need to integrate into the ecosystem we are building.”

“Jun Wang and iCarbonX are at the forefront of the transformation of healthcare that we and many others are working hard to realize,” said Larry Gold, Chairman and Founder of SomaLogic. “All of us at SomaLogic are excited that Jun and his colleagues recognize the primary contribution of proteomic information in bringing about that transformation, and that they have selected our technology and scientists to partner with them in making it happen.”

Under this new agreement SomaLogic and iCarbonX will establish a joint venture in China, which will include installing SomaLogic’s SOMAscan proteomics assay in China to support the Digital Life Alliance as well as many other Chinese research and clinical concerns. “The joint venture with our iCarbonX colleagues significantly expands SomaLogic’s global reach,” said Byron Hewett, SomaLogic’s Chief Executive Officer. “iCarbonX is the best partner possible for helping us gain access to the enormous Chinese healthcare-related markets.”

Through the ecosystem it is building, iCarbonX has made a substantial equity investment in SomaLogic, but specific financial details were not released.

Earlier today at the 1st Digital Life Summit & Digital Life Alliance Global Recruitment Conference in Shenzhen, China, Wang announced that Somalogic and six other companies and organizations are founding members of iCarbonX’s Digital Life Alliance. SomaLogic, HealthTell, PatientsLikeMe, GALT, Inc. , Robustnique and AOBiome join Imagu Vision Technologies, which iCarbonX acquired in September 2016

About SomaLogic

SomaLogic is transforming healthcare by applying our proprietary protein-measurement technology to enable the precise monitoring of each individual’s health and wellness status in real time. We work with many different partners across research, health management, pharmaceutical development, and other health-related fields to build applications on our “Wellness Chip Platform,” a single cost-effective and reliable testing platform that provides actionable and timely information to patients and healthcare providers across a wide range of diseases and conditions. Our SOMAmer® and SOMAscan® technologies also have multiple applications across the life sciences, and are available to the entire biomedical scientific community for their own research needs. For more information, visit www.somalogic.wpengine.com.

Contact information

Fintan R. Steele, Ph.D., VP, Corporate Communications

fsteele@somalogic.com

+1 720-214-3080 – T

+1 617-816-9834 – M