Douglas M. Sheeley, Sc.D., NIH Common Fund
Revolutionizing Technology to Treat Genetic Diseases: The NIH TARGETED Challenge
Posted on by Lawrence Tabak, D.D.S., Ph.D. and Douglas M. Sheeley, Sc.D., NIH Common Fund
Recent scientific advances in the field of genome editing, which enables precise modifications to DNA, have greatly increased the potential to treat genetic diseases. Despite revolutionary progress in this area, treatment options remain limited. Several scientific challenges must be addressed before gene editing can be widely used in the clinic. For example, gene editing tools may cut in unintended areas in addition to the target site, and more research is necessary to understand how these errors affect patients.
Another key challenge is that many organs remain difficult to reach with gene therapies because we do not have adequate ways to deliver gene editing tools to all cells. While efficient delivery technologies exist for some targets, like liver cells, novel and specialized delivery methods designed for specific cell types and locations in the body are needed to ensure genome editing tools can reach sufficient numbers and types of somatic cells to modify DNA safely and effectively. Somatic cell gene therapies target non-reproductive cells, so the changes only affect the person who receives the gene therapy and are not passed down generation to generation.
To address these challenges, NIH launched the TARGETED (Targeted Genome Editor Delivery) Challenge, a multi-phase competition funded through the NIH Common Fund as part of the NIH Somatic Cell Genome Editing (SCGE) Program. SCGE was funded in 2018 to improve the efficacy and specificity of genome editing to help reduce the burden of common and rare diseases caused by genetic changes.
As part of the TARGETED Challenge, research teams will develop technologies for delivering genome editors to somatic cells. NIH will award up to $6 million in prize money across the challenge.
The Challenge is focused on finding delivery systems that can be programmed with biological or chemical tags that correspond to specific target cells and tissues. These tags would direct the delivery systems and the genome editing therapies to the target cells or tissues—like mail being delivered to different zip codes. Such programmable delivery systems would improve gene editing efficacy by targeting diseases at their source and would enhance safety by reducing undesired impacts on other tissues or cells. Ultimately, the development of safe and effective programmable delivery technologies for genome editors that are applicable to multiple diseases would help advance the application of gene editing therapies into the clinic.
The Challenge also is interested in gene editing delivery technologies that can cross the blood-brain barrier (BBB). The BBB protects the brain by blocking harmful substances from entering the fluid of the central nervous system. Unfortunately, it also blocks the uptake of many therapeutics, hindering treatments for brain diseases. While viruses are one of the few approaches that can be used as delivery systems to cross the BBB, they are expensive and difficult to make. Therefore, there is a pressing need for effective non-viral technologies to deliver genome editing machinery across the BBB to a substantial proportion of clinically relevant brain cell types. Such technologies could have broad implications for the treatment of many neurogenetic diseases.
Solutions to both target areas would not only provide proof-of-concept for the delivery of genome editing therapeutics, but they could be adapted to deliver other types of therapies to treat common and rare diseases in general.
The first phase of the Challenge began on May 15, 2023 and will run until October 5, 2023. More information about the Challenge is available on the TARGETED Genome Editor Delivery Challenge website.
Links:
“National Institutes of Health launch TARGETED Challenge,” NIH Common Fund, May 15, 2023
TARGETED Genome Editor Delivery Challenge (NIH Common Fund)
Somatic Cell Genome Editing Program (NIH Common Fund)
NIH Support: The SCGE program is led by the NIH Common Fund, the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS). The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the National Heart, Lung, and Blood Institute (NHLBI) are also contributors to this Challenge.
New Tool Predicts Response to Immunotherapy in Lung Cancer Patients
Posted on by Douglas M. Sheeley, Sc.D., NIH Common Fund
With just a blood sample from a patient, a promising technology has the potential to accurately diagnose non-small cell lung cancer (NSCLC), the most-common form of the disease, more than 90 percent of the time. The same technology can even predict from the same blood sample whether a patient will respond well to a targeted immunotherapy treatment.
This work is a good example of research supported by the NIH Common Fund. Many Common Fund programs support development of new tools that catalyze research across the full spectrum of biomedical science without focusing on a single disease or organ system.
The emerging NSCLC prediction technology was developed as part of our Extracellular RNA Communication Program. The program develops technologies to understand RNA circulating in the body, known as extracellular RNA (exRNA). These molecules can be easily accessed in bodily fluids such as blood, urine, and saliva, and they have enormous potential as biomarkers to better understand cancer and other diseases.
When the body’s immune system detects a developing tumor, it activates various immune cells that work together to kill the suspicious cells. But many tumors have found a way to evade the immune system by producing a protein called PD-L1.
Displayed on the surface of a cancer cell, PD-L1 can bind to a protein found on immune cells with the similar designation of PD-1. The binding of the two proteins keeps immune cells from killing tumor cells. One type of immunotherapy interferes with this binding process and can restore the natural ability of the immune system to kill the tumor cells.
However, tumors differ from person to person, and this form of cancer immunotherapy doesn’t work for everyone. People with higher levels of PD-L1 in their tumors generally have better response rates to immunotherapy, and that’s why oncologists test for the protein before attempting the treatment.
Because cancer cells within a tumor can vary greatly, a single biopsy taken at a single site in the tumor may miss cells with PD-L1. In fact, current prediction technologies using tissue biopsies correctly predict just 20 – 40 percent of NSCLC patients who will respond well to immunotherapy. This means some people receive immunotherapy who shouldn’t, while others don’t get it who might benefit.
To improve these predictions, a research team led by Eduardo Reátegui, The Ohio State University, Columbus, engineered a new technology to measure exRNA and proteins found within and on the surface of extracellular vesicles (EVs) [1]. EVs are tiny molecular containers released by cells. They carry RNA and proteins (including PD-L1) throughout the body and are known to play a role in communication between cells.
As the illustration above shows, EVs can be shed from tumors and then circulate in the bloodstream. That means their characteristics and internal cargo, including exRNA, can provide insight into the features of a tumor. But collecting EVs, breaking them open, and pooling their contents for assessment means that molecules occurring in small quantities (like PD-L1) can get lost in the mix. It also exposes delicate exRNA molecules to potential breakdown outside the protective EV.
The new technology solves these problems. It sorts and isolates individual EVs and measures both PD-1 and PD-L1 proteins, as well as exRNA that contains their genetic codes. This provides a more comprehensive picture of PD-L1 production within the tumor compared to a single biopsy sample. But also, measuring surface proteins and the contents of individual EVs makes this technique exquisitely sensitive.
By measuring proteins and the exRNA cargo from individual EVs, Reátegui and team found that the technology correctly predicted whether a patient had NSCLC 93.2 percent of the time. It also predicted immunotherapy response with an accuracy of 72.2 percent, far exceeding the current gold standard method.
The researchers are working on scaling up the technology, which would increase precision and allow for more simultaneous measurements. They are also working with the James Comprehensive Cancer Center at The Ohio State University to expand their testing. That includes validating the technology using banked clinical samples of blood and other bodily fluids from large groups of cancer patients. With continued development, this new technology could improve NSCLC treatment while, critically, lowering its cost.
The real power of the technology, though, lies in its flexibility. Its components can be swapped out to recognize any number of marker molecules for other diseases and conditions. That includes other cancers, neurodegenerative diseases, traumatic brain injury, viral diseases, and cardiovascular diseases. This broad applicability is an example of how Common Fund investments catalyze advances across the research spectrum that will help many people now and in the future.
Reference:
[1] An immunogold single extracellular vesicular RNA and protein (AuSERP) biochip to predict responses to immunotherapy in non-small cell lung cancer patients. Nguyen LTH, Zhang J, Rima XY, Wang X, Kwak KJ, Okimoto T, Amann J, Yoon MJ, Shukuya T, Chiang CL, Walters N, Ma Y, Belcher D, Li H, Palmer AF, Carbone DP, Lee LJ, Reátegui E. J Extracell Vesicles. 11(9):e12258. doi: 10.1002/jev2.12258.
Links:
Video: Unlocking the Mysteries of Extracellular RNA Communication (Common Fund)
Extracellular RNA Communication Program (ERCC) (Common Fund)
Upcoming Meeting: ERCC19 Research Meeting (May 1-2, 2023)
Eduardo Reátegui Group for Bioengineering Research (The Ohio State University College of Engineering, Columbus)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 27th in the series of NIH guest posts that will run until a new permanent NIH director is in place.
