CTSA Program Supports New Ultrasensitive Diagnostic Test Development

Stanford University researchers have developed a new assay (test) for diagnosing diseases, including thyroid cancer, HIV and type 1 diabetes. The method appears to be many times more sensitive than some traditional diagnostic tests, meaning that it potentially can detect illnesses earlier, enabling clinicians to treat patients sooner and possibly slow disease progression.

Jason Tsai and Peter Robinson

Jason Tsai and Peter Robinson, two of three co-founders of Enable Biosciences, are investigating the synthesis of reagents for their ultrasensitive antibody detection platform. Enable is developing tests for HIV and type 1 diabetes that are 1,000 times more sensitive than current methods. (Stanford University News Photo/L.A. Cicero)

The research, led by recent Ph.D. graduate Peter Robinson and Ph.D. candidate Jason Tsai under the guidance of Carolyn Bertozzi, Ph.D., professor of chemistry, radiology and chemical and systems biology, was supported in part by a Stanford Predictives and Diagnostics Accelerator (SPADA) pilot grant. The SPADA program is part of the Stanford Center for Clinical and Translational Research and Education (also referred to as Spectrum), an NCATS Clinical and Translational Science Awards (CTSA) Program hub. SPADA pilot grants support research to translate discoveries into novel predictive and diagnostic products that address unmet medical needs. The emphasis is on technologies that have the potential to advance rapidly into clinical care through commercialization or other pathways.

“CTSA Program hubs promote excellence and innovation in research resources and training as well as fund opportunities such as the Stanford SPADA program to foster the translation of research discoveries into health benefits,” said Petra Kaufmann, M.D., M.Sc., director, NCATS Division of Clinical Innovation and Office of Rare Diseases Research.

Improving the Status Quo

The Stanford team designed a test to detect antibodies, which are proteins the body produces in response to and for the purpose of counteracting a specific antigen — a toxin or other foreign substance that generates a response from the body’s immune system. Clinicians commonly diagnose abnormal health conditions by testing for specific antibodies that indicate the presence of a particular disease. Current tests detect antibodies using radioactive tags, meaning these tests must be conducted in specially equipped laboratories. Many hospitals lack these facilities, so staff must send samples to outside laboratories, which can be costly and time-consuming.

The new test uses small DNA fragments to identify and “tag” antibodies. Standard polymerase chain reaction (PCR) technology is then used to quickly amplify small segments of DNA, which enables clinicians and researchers to analyze and measure the tagged antibodies. PCR is a decades-old, relatively inexpensive technology that can be deployed easily in most standard laboratories. An advantage of the new assay, called antibody detection by agglutination-PCR (ADAP), is that the lack of radioactivity and easy access to PCR technology mean ADAP can be performed in most hospitals, enabling more clinicians to receive diagnostic results sooner.

ADAP also appears to be more sensitive than some traditional tests. Robinson explained that it can detect antibodies at much lower levels than standard techniques, meaning it could help clinicians diagnose and treat diseases at earlier stages. The researchers demonstrated that ADAP detected thyroid cancer antibodies with 1,000 times the sensitivity of the current test approved by the Food and Drug Administration. They published this work in the Feb. 16, 2016, issue of ACS Central Science.

After establishing the assay’s validity, Robinson and Tsai began adapting it to detect early-stage HIV infection by testing saliva, which is ideal for large-scale public health screening because it is cheap and noninvasive. HIV is most infectious during the first several weeks after exposure; however, current saliva tests lack the sensitivity to detect the virus at this stage.

Using preliminary data showing that ADAP could detect HIV antibodies accurately in patients’ oral fluid samples, Robinson and Tsai secured the SPADA pilot grant from the Stanford CTSA/Spectrum Pilot Grant Program in spring 2016. The team is using the funding to collect and analyze additional samples to validate initial findings. The next step will be to determine if ADAP can outperform current saliva tests by accurately detecting HIV antibodies at early stages of infection.

The team envisions expanding the technology to diagnose a wide range of other diseases. Additionally, the test could be adapted for use in basic science research to discover new antibodies, which could lead to diagnostic tests for diseases that are currently difficult to diagnose. For now, the researchers are focused on further validating and optimizing the assay to generate marketable products for early detection of thyroid cancer and HIV as well as type 1 diabetes.

A Path to Commercialization

Co-founders and advisory board of Enable Biosciences

The co-founders and advisory board members of Enable Biosciences: Dr. Peter Robinson, Co-Founder and CSO of Enable Bioscience; Stephanie Marrus, Director of the Entrepreneurship Center at UCSF; Prof. Carolyn Bertozzi, Department of Chemistry and HHMI, Stanford University, Co-Founder and consultant to Enable Bioscience; Jason Tsai, co-Founder and CTO of Enable Bioscience; Dr. David Seftel, Co-Founder and CEO of Enable Bioscience; Dr. Mark Pandori, Associate Clinical Professor, Department of Laboratory Medicine, UCSF, and Director, Alameda County Public Health Laboratory. (Stanford University Photo/Peter Robinson) (Stanford University Photo/Peter Robinson)

Within the SPADA framework, young investigators receive advice during quarterly project review meetings with faculty, industry volunteers and peers. This approach helps keep projects on schedule and following a translational path that is more likely to lead to products that can be used in the clinic.

The research team’s early data enabled Bertozzi, Robinson and Tsai to establish a company called Enable Biosciences in late 2015. They also enlisted the services of biotech entrepreneur David Seftel, M.D., M.B.A., who now serves as the chief executive officer of the company. Enable received a Small Business Innovation Research award from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases to develop the test to diagnose type 1 diabetes. Enable researchers also received a technology development award from the National Science Foundation that they will use to adapt the diagnostic platform to detect many types of antibodies at once. This step is essential because for many conditions, clinicians can confirm a diagnosis only if several different disease-specific antibodies are present.

“SPADA is a fantastic program that helps Stanford faculty and trainees collect important datasets that serve as a foundation for the development of marketable diagnostic products,” Bertozzi said. “It is quite difficult to find funds for those kinds of activities, so having a program explicitly focused on seeding entrepreneurship and start-up companies is immensely valuable.”

“Our goal,” Bertozzi added, “is to deliver a world-class technology that ultimately will improve the lives of patients.”


Posted September 2016