Published examples of how the SomaScan technology can help COVID-19 researchers


Below are specific examples tied to use cases for the SomaScan Assay in helping to address the COVID-19 pandemic.

USE CASE 1: Learning how to predict early who is going to progress and develop severe illness from the disease

Action: Discover protein expression patterns in patients with mild/moderate symptoms that can provide the basis for developing a rapid diagnostic test to identify who will go on to develop life-threatening illness, and who won’t.

Relevant publications USE CASE 1:

"Plasma Protein Patterns as Comprehensive Indicators of Health." Williams, SA et al. (2019) Nat Med 25(12): 1851-1857.

https://www.ncbi.nlm.nih.gov/pubmed/31792462

In this article, an international team led by researchers from the University of California San Francisco, University of Cambridge and SomaLogic describes how information about a person’s current health status, modifiable behaviors and future risks of cardiometabolic disease can be discerned entirely from different patterns of proteins their blood. The results show how scanning the levels of thousands of plasma proteins simultaneously could capture enough information to deliver a one-stop, “liquid health check” for personalized detection, prevention and treatment of disease.

The work is a new milestone for large-scale protein scanning, with a total of approximately 85 million individual protein measurements and for the first time, evaluating proteins alone as the single source of medical information. Using the SomaScan Platform, the levels of approximately 5000 proteins were measured in each archived plasma sample from nearly 17,000 participants in 5 well-characterized patient groups. Applying sophisticated computer algorithms to the massive data set in rigorously pre-defined analyses revealed protein patterns that correlated with medical information provided with the blood sample, such as the results of a liver ultrasound, a treadmill test or whether the patient later suffered a heart attack or developed diabetes.

Out of 13 different health indicators examined, 11 protein-based models were developed that could successfully predict: presence/absence of liver fat; kidney function; percent body fat; visceral fat; lean body mass; cardiopulmonary fitness; average daily physical activity; alcohol consumption; cigarette smoking; diagnosis of diabetes in pre-diabetics within 10 years; and likelihood of heart attack, stroke, heart failure or cardiovascular death within 5 years in people without known heart disease. The accuracy of the protein-based models varied, but all were either better predictors than models based on traditional risk factors or would constitute more convenient alternatives to traditional testing.

"Discovery and Validation of a Prognostic Proteomic Signature for Tuberculosis Progression: A Prospective Cohort Study." Penn-Nicholson, A et al. (2019) PLoS Med 16(4): e1002781.

https://www.ncbi.nlm.nih.gov/pubmed/31792462

One third of the world’s population have tuberculosis (TB) bacteria lying dormant in their bodies. However, only five to ten percent of those with latent TB will go on to develop active disease. Identifying those individuals is critical for controlling the spread of new infections and for focusing precious treatment resources. An international team led by scientists at the University of Cape Town used the SomaScan Assay to measure the levels of 3040 proteins in plasma collected from TB-infected South African adolescents. They identified 135 proteins that were significantly different between those who progressed to active TB compared to those who did not. The researchers successfully validated two different sets of proteins that could predict the subset who went on to develop active TB within a year. Although more work is needed to meet the threshold of performance criteria defined by the World Health Organization, the results suggest that a blood-based protein test for determining TB progression is possible.

"Plasma Proteome Analysis in Patients with Pulmonary Arterial Hypertension: An Observational Cohort Study." Rhodes, CJ et al. (2017) Lancet Respir Med 5(9): 717-726.

https://www.ncbi.nlm.nih.gov/pubmed/31792462

In this multicenter study, researchers from the UK, France and Germany used the SomaScan Assay to measure the levels of 1,129 proteins in blood samples from patients with pulmonary arterial hypertension (PAH). PAH is a rare, incurable disease where the small arteries in the lung progressively narrow, and the heart is forced to pump harder and harder until it eventually fails. The investigators identified nine proteins that differentiated PAH survivors from non-survivors and used this protein panel to develop a risk score that predicted patient survival better than existing clinical tests. The protein-based risk score was then validated on two separate patient cohorts, including one that contained 43 paired plasma samples taken when PAH was first diagnosed and after treatment. Increased risk scores at follow-up correlated with poorer survival rates and outperformed established measures. These results suggest that the nine-protein risk score could be used to monitor PAH progression, assess treatment efficacy and stratify patients in clinical trials. Further investigation of the proteins that make up the panel may provide insights into the causes of PAH and possible therapeutic targets.

"Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants." Wagner, BD et al. (2017) Am J Respir Crit Care Med 197(3): 394-397.

https://www.ncbi.nlm.nih.gov/pubmed/28650220

Many premature babies are diagnosed with pulmonary vascular disease (PVD), which is characterized by abnormal blood flow between the heart and lungs. In this study from the University of Colorado Denver, the SomaScan Assay was used to measure proteins in blood samples from 100 preterm infants, 44 of which had PVD. Researchers identified 18 proteins that a week after birth could distinguish babies who developed PVD from those who did not. Eight of these proteins had no previous association with PVD. Although preliminary, these results may provide insight into why some infants develop respiratory problems, and how these problems contribute to lung diseases in adulthood. The authors note that the SomaScan is particularly well-suited for neonatal studies since only a small amount of blood (50uL serum) is needed to measure >1000 proteins.

"Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease." Ganz, P et al. (2016) JAMA 315(23): 2532-2541.

https://www.ncbi.nlm.nih.gov/pubmed/28650220

Every patient diagnosed with stable coronary heart disease is currently treated aggressively in order to help prevent any future cardiovascular events. However, not every such individual is at significant risk of such events, leading to expensive overtreatment and mental anguish. In this breakthrough study, researchers from UCSF and SomaLogic used SomaScan to discover and validate a group of nine blood proteins whose levels can reliably and accurately predict who is at high or low risk of future events. These proteins can also be used to track who is getting closer to an event, and who is benefitting from preventative interventions. The accompanying editorial by Dr. Marc Sabatine from Harvard puts these findings in the context of emerging personalized or precision medicine, as well as the possibility that several of the novel proteins uncovered could be future therapeutic targets.

 

 

USE CASE 2: Identifying disease complication sub-types in those at risk for severe illness

Action: Discover protein expression patterns in patients that will become the basis of a test to help doctors determine which patient will develop specific clinical complications – e.g., respiratory failure alone, respiratory failure with cardiac myopathy, or other complications. Similarly to Use Case 1, these protein signatures can provide the basis for developing a rapid diagnostic test that can translate findings into patient care.

Relevant publications USE CASE 2:

"A Signature of Circulating Inflammatory Proteins and Development of End-Stage Renal Disease in Diabetes." Niewczas, MA et al. (2019) Nat Med 25(5): 805-813.

https://www.ncbi.nlm.nih.gov/pubmed/31792462

Diabetes is the leading cause of kidney disease worldwide, and diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD). Chronic inflammation is believed to contribute to the progression of DKD to ESRD, although it is unclear how. To better understand the link between inflammation and DKD outcomes, an international team led by researchers at the Joslin Diabetes Center and Harvard University used a custom version of the SomaScan Assay to measure the levels of 194 circulating inflammatory proteins in samples collected from a group of 219 patients with type 1 diabetes and impaired kidney function. They found significantly higher levels of 35 proteins in individuals who later developed ESRD, and validated 17 of the identified proteins in a group of 162 patients with type 2 diabetes. Sixteen of the 17 validated proteins were then replicated in a cohort of Pima Indians with normal renal function at the time of sample collection, which suggests that these proteins represent a kidney risk inflammatory signature (KRIS). Unexpectedly, the researchers found that the high levels of KRIS proteins originated outside of the kidney, which implies that DKD progression involves inflammation occurring in other parts of the body. Since the KRIS proteins are elevated in patients with different types of diabetes, different levels of kidney function and different ethnicities, they may prove to be universal markers of DKD that could be used to identify new therapeutic targets, predict risk of ESRD progression and measure response to treatments.

"Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus Aureus Antigens, and Underlying Systemic Inflammation." Leonard, A et al. (2019) J Allergy Clin Immunol Pract., 8(1):236-247

https://www.ncbi.nlm.nih.gov/pubmed/31792462

Atopic dermatitis, the most common type of eczema, is a chronic skin condition in which itchy rashes periodically flare up. People with atopic dermatitis are more likely to develop allergies and some studies have suggested that those with allergies may have a different subtype of the disease that could benefit from more targeted treatments. In this article, researchers from MedImmune and the Icahn School of Medicine at Mount Sinai conducted allergy testing on blood samples taken from 76 people with moderate to severe atopic dermatitis compared to 39 healthy controls. In parallel, they measured the levels of 1129 proteins in the blood samples using the SomaScan Assay and found that different proteins were increased in those with atopic dermatitis depending on the type of allergies they had (i.e. food, seasonal, perennial or mixed). These protein inflammatory signatures could be valuable for more precisely characterizing atopic dermatitis patients and determining the best therapies for them.

"Plasma Proteomics Identifies a 'Chemokine Storm' in Idiopathic Multicentric Castleman Disease." Pierson, SK et al. (2018) Am J Hematol 93(7): 902-912.

https://www.ncbi.nlm.nih.gov/pubmed/29675946

Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening disorder characterized by enlarged lymph nodes and a wide variety of severe symptoms. iMCD disease progression is believed to be driven by uncontrolled release of proinflammatory proteins, particularly interleukin 6 (IL-6), however most iMCD patients do not respond to IL-6-blocking treatments. To better understand the pathogenesis of iMCD, a team led by researchers at the University of Pennsylvania used the SomaScan Assay to measure the levels of 1129 plasma proteins in six iMCD patients. They found that the protein profiles during disease flare and remission were quite distinct, and that chemokines—proteins that attract white blood cells to sites of infection—were more highly enriched during flares than interleukins or other proinflammatory proteins. Two of the patients belonged to a separate clinical subtype and could be distinguished from the others by their distinct protein profiles. Both patients failed to respond to anti-IL-6 therapies, which suggests that different disease mechanisms exist and that measuring plasma protein levels may aid diagnosis and direct treatment of iMCD subgroups.

"The Peripheral Blood Proteome Signature of Idiopathic Pulmonary Fibrosis is Distinct from Normal and is Associated with Novel Immunological Processes." O'Dwyer, DN et al. (2017) Sci Rep 7: 46560.

https://www.ncbi.nlm.nih.gov/pubmed/28440314

Idiopathic pulmonary fibrosis (IPF) is a fatal condition characterized by scar tissue that builds up in the lungs, making it harder and harder to breathe. The course of the disease is highly variable, and the cause is usually unknown, which makes it difficult to devise appropriate interventions. Previously, a team led by University of Michigan researchers used the SomaScan Assay to develop a six-protein panel that was able to predict IPF disease progression (Ashley, SL et al. (2016) PLoS One 11(8): e0159878; https://doi.org/10.1371/journal.pone.0159878). The goal of this new study was to see if circulating proteins could shed light on the disease biology of IPF. The researchers used the SomaScan Assay to compare protein levels in blood from IPF and healthy patients and identified 164 proteins that differed significantly between the two groups. The identified proteins play roles in the defense response, wound healing and protein phosphorylation, which should be helpful for finding new drug targets for treating IPF. Eight proteins were sufficient to distinguish IPF patients from normal controls, which could lead to a minimally invasive way to differentiate IPF from other chronic lung diseases.

 

 

USE CASE 3: Repurpose existing approved drugs by matching them with identified biological drivers of downstream effects of COVID-19

Action: Discover protein expression patterns that show which dominant biological systems are driving adverse secondary effects of infection; match these to the mechanisms of existing drugs; translate into patient care.

Relevant publications USE CASE 3:

"Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial." Demidowich, AP et al. (2020) Int J Obes (Lond), epub ahead of print.

https://www.ncbi.nlm.nih.gov/pubmed/32196559

A clinical trial conducted by researchers at the National Institutes of Health and Johns Hopkins School of Medicine found that colchicine, an anti-inflammatory medication used to treat gout, had beneficial effects in adults at high risk of developing cardiometabolic disease. To gain insight into colchicine’s mechanisms of action, the researchers used the SomaScan Assay to measure the levels of 1305 proteins in blood taken from 40 obese adults with metabolic syndrome before and after three months of treatment with either colchicine or placebo. Colchicine significantly altered the levels of 34 proteins, reducing the levels of many involved in inflammation, including interleukin-6 (IL-6). High IL-6 levels are associated with poor outcomes in COVID-19 patients, and the authors state that, “Further research is warranted to investigate whether colchicine’s IL-6 suppressive effects may be beneficial in COVID-19.”

"Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL." Guerrero, CLH et al. (2020) Blood Adv 4(6): 1062-1071.

https://www.ncbi.nlm.nih.gov/pubmed/32196559

Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive cancer that occurs in people infected with human T-lymphotropic virus type 1 (HTLV-1). Only about five percent of those with HTLV-1 develop ATL, but there is currently no way to distinguish those who will progress to disease. In this study, scientists in Japan used the SomaScan Assay to measure the levels of 1305 proteins in plasma taken from 40 people with asymptomatic HTLV-1, 40 people with ATL and five people in remission. They identified 333 proteins that were significantly different between those with and without ATL and confirmed by ELISA that one protein, soluble tumor necrosis factor 2 (sTNFR2) was ten times higher in those with ATL than in HTLV-1 carriers and those in remission. Additional studies in larger patient groups is needed, but sTNFR2 could be a candidate biomarker for diagnosing ATL, assessing disease risk and monitoring treatment efficacy.

"Fatigue in Sjögren's Syndrome: A Search for Biomarkers and Treatment Targets." Bodewes, ILA et al. (2019) Front Immunol 10: 312.

https://www.ncbi.nlm.nih.gov/pubmed/30863411

Primary Sjögren’s syndrome (pSS) is a disease in which the immune system attacks the salivary glands. In addition to dry mouth and dry eyes, one of the most common symptoms of pSS is debilitating fatigue. To gain insight into the causes of fatigue in pSS sufferers, researchers at Erasmus University Medical Center in the Netherlands used the SomaScan Assay to compare the levels of 1300 proteins in blood samples taken from 63 pSS patients and 20 healthy controls. A total of 104 proteins were significantly different between the two groups, and 16 proteins were significantly different between fatigued and non-fatigued patients. When possible, the proteins identified by SomaScan were validated using conventional antibody-based techniques, which showed good correlations and reliability. Fatigued pSS patients showed increased levels of several proteins that promote inflammation as well as various proteins that function in the brain. Although proinflammatory processes have been suspected to play a role in fatigue, this is the first evidence of a link in pSS. The ‘fatigue signature’ proteins need to be validated in larger cohorts but could be very useful for identifying therapeutic targets and developing potential treatments for those with pSS.

“Benefit of Apabetalone on Plasma Proteins in Renal Disease.” Wasiak, S et al. (2018) Kidney International Reports 3(3): 711-721.

https://www.sciencedirect.com/science/article/pii/S2468024917304576

Bromodomain and Extra-Terminal domain (BET) proteins, which help turn specific genes on and off, are important drug targets for a wide range of conditions including cancer, neurological disorders and obesity. Apabetalone, a BET inhibitor under development to treat cardiovascular disease, can reduce renal inflammation in patients with severely impaired kidney function. To better understand the effects of apabetalone, a team led by investigators at Resverlogix Corp. compared the levels of circulating proteins in healthy patients and those with chronic kidney disease (CKD). Blood samples from eight people with CKD and eight matched controls were collected before and after taking apabetalone and analyzed using the SomaScan Assay. The levels of 169 proteins differed significantly in CKD patients compared to controls. Many of the identified proteins are well-established markers of kidney function but some are entirely new. Within 12 hours, a single dose of apabetalone significantly lowered the levels of proteins that contribute to inflammation, atherosclerosis and fibrosis. These results suggest that apabetalone may be useful for treating not just CKD, but multiple diseases in which the BET proteins play a role.

"Trisomy 21 Causes Changes in the Circulating Proteome Indicative of Chronic Autoinflammation." Sullivan, KD et al. (2017) Sci Rep 7(1): 14818.

https://www.ncbi.nlm.nih.gov/pubmed/29093484

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.

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 165 Down syndrome patients and compared them to 98 non-Down syndrome controls. 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 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.

 

 

USE CASE 4: Rapidly identify protein targets for new drug candidates to address the effects of COVID-19

Action: Discover new drug targets by relating changes in individual proteins to disease severity and prognosis (often in conjunction with genomic information); enable Pharma to act upon the results.

Relevant publications USE CASE 4:

"Co-Regulatory Networks of Human Serum Proteins Link Genetics to Disease." Emilsson, V et al. (2018) Science 361(6404): 769-773.

https://www.ncbi.nlm.nih.gov/pubmed/30072576

In this article, researchers from Novartis and the Icelandic Heart Association demonstrated that communication between networks of proteins can explain the connections between genes and complex disorders, such as heart disease and diabetes. They began with an established Icelandic study of aging (AGES-Reykjavik), which initially focused on understanding the role of genetic variations in late-onset, age-related diseases. Participants in AGES-Reykjavik were over 65 and included both healthy adults and those diagnosed with various conditions of old age. However, linking individual gene variants to disease proved almost impossible since common chronic conditions of aging are not caused by defects in a single gene.

In the study, the research teams used a custom version of the SomaScan Assay to measure the levels of over 4,000 different human proteins in 5,457 blood samples from individuals in the AGES-Reykjavik study. Using advanced computational tools to mine approximately 27 million protein measurements, the researchers found that the examined proteins clustered into 27 different groups or “networks” composed of 20 to 921 proteins. Each network contained a few central players that were highly connected, and these “hub proteins” seemed to organize interactions and information flow within the network. When investigators incorporated genetic data on AGES participants, they found that the hub proteins were often regulated by genetic variations that had been previously linked to cardiovascular and metabolic diseases, but for which the biological underpinnings were unknown.

These findings show how the thousands of proteins detectable in the blood can facilitate communication between the various cells, tissues and organs of the body. Using the SomaScan Assay to “listen into” these communication networks may reveal new ways to detect, predict, monitor and even treat common age-related disorders.

“Genomic Atlas of the Human Plasma Proteome.” Sun, BB et al. (2018) Nature 558: 73-79.

https://www.ncbi.nlm.nih.gov/pubmed/29875488

Over the past decade, genome-wide association studies (GWAS) have identified thousands of DNA variants that are linked to complex traits and diseases but have not explained exactly why they are important. The vast majority of DNA differences flagged by GWAS lie in regions of the genome with no known function and have small effect sizes. This surprising finding makes establishing causal relationships or determining disease risk extremely difficult, even for conditions with a strong hereditary component such as obesity or cancer.

In the largest study of its kind to-date, an international team led by researchers from the University of Cambridge and Merck used the SomaScan Assay to measure the levels of 2,994 plasma proteins and compared those levels with 10.6 million DNA variants across 3,301 healthy individuals of European heritage. They identified 1,927 genetic variants that impact the levels of 1,478 plasma proteins, of which approximately 90% had not been previously reported. Many of the variants act in “trans” (i.e., they lie far from the gene whose activity is altered, typically on different chromosomes). Trans associations are particularly interesting because they can highlight biological connections that are difficult to predict otherwise.

"Genetic Architecture of the Cardiovascular Risk Proteome." Benson, MD et al. (2018) Circulation 137(11): 1158-1172.

http://circ.ahajournals.org/content/137/11/1158.long

Changes in protein levels reflect the functional consequences of gene variants and can help establish hereditary causes of disease. Previously, investigators at the Beth Israel Deaconess Medical Center used the SomaScan Assay to identify 156 plasma proteins that associated with clinical risk factors for developing cardiovascular disease (CVD)—age, sex, cholesterol, blood pressure, diabetes, and smoking (ref: Ngo, D et al. (2016) Circulation 134(4): 270-285; https://doi.org/10.1161/CIRCULATIONAHA.116.021803). In this study, the researchers integrated genomic data into their SomaScan-based proteomic profiling and found a number of new connections between gene variants and circulating proteins that are important in CVD. One of the DNA-protein associations led to the discovery that the gene for protein phosphatase 1 (PPM1G) regulates the levels of apolipoprotein E, a cholesterol transporter. This is the first time that PPM1G has been linked to lipid metabolism. The authors have made their gene variant-protein association data publicly available, which should hasten the discovery of additional insights into CVD biology, potential biomarkers and putative drug targets.

"Application of Large Scale Aptamer-Based Proteomic Profiling to "Planned" Myocardial Infarctions." Jacob, J et al. (2017) Circulation 137(12): 1270-1277.

https://www.ncbi.nlm.nih.gov/pubmed/29222138

In this study, researchers at the Novartis Institute for BioMedical Research, Beth Israel Deaconess Medical Center, and Brigham and Women’s Hospital used the SomaScan Platform to measure the levels of approximately 5,000 proteins in blood samples taken from patients undergoing a “planned” heart attack, a medical procedure that can help reduce severely overgrown heart muscle (hypertrophic cardiomyopathy). They analyzed plasma taken before and at different time points after the procedure, looking for proteins whose levels changed significantly. Their results not only confirmed findings from a prior study that used an earlier, smaller version of the SomaScan Platform (ref: Ngo, D et al. (2016) Circulation 134(4): 270-285; https://doi.org/10.1161/CIRCULATIONAHA.116.021803) but also identified nearly 150 new proteins, many of which had not been previously associated with heart damage. Twenty-nine of the proteins that were significantly increased within an hour after a planned heart attack were also elevated in patients who suffered “unplanned” heart attacks.

This article is the first published description of large-scale protein profiling at a level that has not previously been reported. The expanded SomaScan Assay platform provides opportunities for unbiased discovery of disease markers to improve diagnosis, predict future events, monitor responses to therapies and identify targets for drug development. Ongoing studies by these authors are applying this expanded SomaScan Platform to larger groups of patients.

 

 

USE CASE 5: Accelerate clinical trials and provide early indication of efficacy of new COVID-19 drug candidates

Action: Apply protein expression patterns discovered in Use Cases 1 and 2 (relating to severity, prognosis and sub-phenotype) in clinical trials to rapidly determine whether a drug will be effective, or not. Protein patterns discovered during these studies can also be used to demonstrate mechanistic proof-of-concept, exposure response (for dose setting), and the existence of undesirable off-target effects.

Relevant publications USE CASE 5:

"Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib." Williams, SA et al. (2018) Circulation 137(10): 999-1010.

http://circ.ahajournals.org/content/137/10/999.long

This article from Pfizer, the University of California, San Francisco, the Karolinska Institute and SomaLogic demonstrates how monitoring blood-based protein changes in response to experimental therapies could one day improve the efficiency and safety of drug development. Researchers used the SomaScan Assay to measure the levels of 1129 proteins in samples from ILLUMINATE, Pfizer’s phase 3 clinical trial of torcetrapib, a drug candidate for treating heart disease. Torcetrapib raises levels of ‘good’ cholesterol and lowers levels of ‘bad’ cholesterol and was expected to be a blockbuster drug that reduced the risk of serious cardiovascular events such as heart failure and stroke. Instead, an increase in deaths and heart problems was seen in trial subjects taking torcetrapib, and ILLUMINATE was abruptly terminated. This happened in 2006 after Pfizer had invested 15 years and nearly a billion dollars in torcetrapib development.

The new study used a previously validated nine-protein cardiovascular risk score (Ganz, P et al. (2016) JAMA 315(23): 2532-2541; https://doi.org/10.1001/jama.2016.5951) to successfully predict the harmful effects of torcetrapib after three months of treatment—much earlier than the point at which ILLUMINATE was stopped (approximately 18 months). The work also provides new insights into how torcetrapib acts in the body and possible clues to its toxicity. Analysis of the 200 proteins that changed significantly compared to matched controls revealed that torcetrapib had widespread and unanticipated effects on immunity and inflammation. In addition, changes in eight proteins were linked to synthesis or function of aldosterone, a steroid hormone involved in regulating blood pressure. These results help explain the hypertensive side effects seen early in torcetrapib’s development.

Torcetrapib is a cholesteryl ester transferase (CETP) inhibitor, a drug class that is of considerable interest to the pharmaceutical industry. In addition to Pfizer, both Eli Lilly and Roche had 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 trial to date. This article shows how profiling proteins could provide early warning of off-target effects and help speed drug development. It also suggests that these same proteins can be used to monitor the ongoing effectiveness of drug treatment in individuals and populations.

"Phase IIa Trial in Duchenne Muscular Dystrophy Shows Vamorolone is a First-in-Class Dissociative Steroidal Anti-Inflammatory Drug." Conklin, LS et al. (2018) Pharmacol Res 136: 140-150.

https://www.ncbi.nlm.nih.gov/pubmed/30219580

In this article, a team led by researchers at the University of Pittsburgh and ReveroGen Biopharma describes the first-in-patient study of vamorolone, a first-in-class steroidal drug for treatment of Duchenne muscular dystrophy (DMD). DMD is a rare muscle wasting disease that affects primarily young boys. The DMD standard of care is treatment with glucocorticoids, which help slow disease progression but have severe side effects. In a multiple-ascending dose study, vamorolone was safe and well-tolerated in boys with DMD. The SomaScan Assay was used to compare protein levels at baseline and after two weeks of daily vamorolone treatment at four different dose levels. Vamorolone treatment led to decreased serum creatine kinase, a marker of muscle disease activity as well as decreases in levels of inflammatory proteins. These results suggest that vamorolone has a beneficial effect and an anti-inflammatory mechanism of action.

"Serum Pharmacodynamic Biomarkers for Chronic Corticosteroid Treatment of Children." Hathout, Y et al. (2016) Sci Rep 6: 31727.

http://www.nature.com/articles/srep31727

Corticosteroids are used effectively across a large number of diseases and conditions in which inflammation plays at least a partial role. But regular, repeated use can bring along a host of side effects, many of which can be worse than the initial disease or condition. In one particular disease, Duchenne muscular dystrophy (DMD), corticosteroids are a current standard of care, but efficacy gives way to safety issues over time, varying by patient. In this article, a multicenter group of researchers use the SomaScan Assay to identify protein biomarkers of corticosteroid efficacy and side effects, with the goal of developing a diagnostic tool to optimize the use of these powerful treatments in DMD patients—and young patients with other diseases—over time.

"Identification of Pathway-Specific Serum Biomarkers of Response to Glucocorticoid and Infliximab Treatment in Children with Inflammatory Bowel Disease." Heier, CR et al. (2016) Clin Transl Gastroenterol 7(9): e192.

https://www.ncbi.nlm.nih.gov/pubmed/27628422

Inflammatory bowel disease (IBD) is a chronic condition where the body’s immune system attacks its own digestive tract. The goal of most IBD treatments is to achieve remission, however there is increasing evidence that alleviating the symptoms does not ultimately improve outcomes. Repeated colonoscopy can be used to monitor patients’ response to IBD therapies, but the technique is costly, invasive and can be risky, particularly for children. In order to find pharmacodynamic biomarkers of IBD, researchers at the Children’s National Health Center in Washington, D.C. ran the SomaScan Assay on pediatric serum samples obtained before and after treatment with a corticosteroid (prednisone) or a biologic (infliximab) anti-inflammatory drug. They identified 18 proteins and 3 miRNAs whose levels changed in a similar manner (either increased or decreased) for both drugs. Eight of the markers that decreased are associated with inflammation, whereas many that increased are associated with resolving inflammation and tissue damage. With further validation, these protein biomarkers could be used to track treatment, optimize dosing, and accelerate new drug development for IBD patients.

 

 

USE CASE 6: Accelerate vaccine development

Action: Find protein expression patterns that detect or predict clinical response to a vaccine, or immune response, that is compatible with longer-term clinical effect.

Relevant publications USE CASE 6:

"Aptamer Profiling of A549 Cells Infected with Low-Pathogenicity and High-Pathogenicity Influenza Viruses." Coombs, KM et al. (2019) Viruses 11(11).

https://www.ncbi.nlm.nih.gov/pubmed/31694171

Influenza A viruses are a constant threat to public health, causing both seasonal epidemics and global pandemics. Designing safe and effective drugs is difficult because type A flu viruses can mutate quickly and because they can infect animals (such as pigs, birds, bats and horses), evolve and then reemerge in humans. Viruses use the host’s cells to replicate and spread, so identifying host factors that are affected by infection is important for developing anti-viral strategies. In this article, scientists at the University of Manitoba and the Public Health Agency of Canada examined the effects of influenza type A infection on the levels of 1310 host proteins using the SomaScan Assay. They infected human lung cells with five different influenza type A viruses: three H1N1 strains (including the 2009 pandemic strain) and two avian strain (the H5N1 “Bird flu”, and an H7N9 strain with low pathogenicity in birds, but high pathogenicity in humans). Compared to mock-infected cells, the levels of more than 500 proteins were changed significantly by one or more of the viruses, although no protein was changed significantly by all five. The two avian strains showed the largest effects, decreasing the levels of many proteins involved in important cell functions. These results warrant further investigation as they may help explain why the avian flu strains have such high pathogenicity in humans.

"Cytokines IL-17, TNF and IFN-gamma Alter the Expression of Antimicrobial Peptides and Proteins Disparately: A Targeted Proteomics Analysis Using SomaScan Technology." Altieri, A et al. (2018) Vaccines (Basel) 6(3).

https://www.ncbi.nlm.nih.gov/pubmed/30087279

The body produces antimicrobial peptides and proteins (APPs) that can directly kill foreign pathogens and modulate the immune response. To better understand how APPs work in fighting lung infections, researchers at the University of Manitoba used the SomaScan Assay to measure the levels of 39 APPs produced by bronchial cells before and after being stimulated by either interleukin-17 (IL-17), tumor necrosis factor (TNF), or interferon-gamma (IFN-g); three proteins that enhance airway inflammation. TNF and IL-17 caused similar responses, but IFN-g was quite distinct. These results suggest that the presence of different inflammatory proteins can affect APP production and infection control.

"Antiinflammatory Effects of Aprepitant Coadministration with cART Regimen Containing Ritonavir in HIV-Infected Adults." Spitsin, S et al. (2017) JCI Insight 2(19): e95893.

https://www.ncbi.nlm.nih.gov/pubmed/28978797

HIV-infected individuals take antiretroviral therapies to help keep the virus at bay, but still suffer from systemic inflammation and immune dysfunction, which affects their quality of life and ability to survive. In this article, researchers at the Children’s Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania describe a dose and time escalation clinical trial of the anti-inflammatory drug aprepitant on 12 HIV-positive patients. The goal was to see if co-administration of aprepitant with ritonavir (an antiretroviral medication) would safely reduce residual inflammation. The SomaScan Assay was used to assess the global effects of aprepitant and identified 176 plasma proteins whose levels changed after drug treatment. These included proteins involved in inflammation and immune regulation as well as blood, lipid and cholesterol metabolism, which warrant caution and further investigation.