Diverse and Coordinated
Today, the CFIDS Association announced five new research grants as part of its “institute without walls” CFS research program.* The Association has funded more CFS research than any other non-profit to date, and expectations are high following on the success of the last round of grants. As in the past, these grants cover diverse aspects of CFS but have a certain synergy in combination. (For information on other aspects of the research program, see Virtually Reality)
- Body systems covered: immune, HPA axis, central nervous system processing, mechanisms of post-exertional malaise
- Expected outcomes: drug repurposing, biomarker discovery and validation, new treatment directions
- Methods: exercise testing, brain imaging, gene expression, epigenetic changes, brain blood flow measurements, body position, proprietary drug repurposing platform
- Principal investigators new to CFS: Spyros Deftereos (Biovista), Patrick McGowan (University of Toronto, Scarborough)
Peter Rowe (Johns Hopkins Children’s Center) will use a simple test to establish whether central sensitization of the nervous system plays a role in CFS. Central sensitization of the central nervous system results in an amplified response to a stimulus, causing pain and other symptoms. Dr. Rowe has observed that simple position changes, such as a passive leg raise, can bring on symptoms of CFS in patients. This new study will investigate the observation by applying either a real or sham neuromuscular strain to both CFS patients and controls. If only the CFS patients respond to the real strain with increased symptoms, then central sensitization may be involved in CFS. Dr. Rowe’s clinical practice focuses on children and young adults with CFS, but it is unclear from the published materials whether the study population will also be younger patients. Expected outcome: Passive neuromuscular strain could be a cheap and easy clinical biomarker for CFS. It is also possible that manual physical therapy addressing neuromuscular mobility could be used as a treatment to lessen the effects of central sensitization.
Spyros Deftereos (Biovista) will use the company’s proprietary drug repurposing platform to identify new treatments for CFS. Drug repurposing, called “eHarmony for medicine,” looks for FDA-approved drugs that might be repurposed in new ways. For example, Rituximab is currently approved for use in non-Hodgkin’s lymphoma and several other diseases, but shows promise for CFS patients. One huge advantage of this approach is that since the drugs are already approved, the decade-plus required to create a new drug is circumvented. Drug candidates could proceed directly to animal model or early clinical trial research. Biovista will screen all FDA-approved drugs to identify treatments for cognitive impairment and unrefreshing sleep in CFS, as well as other CFS symptoms. Drugs identified will then be examined to see if combination therapy might be more effective than using one drug alone. One thing that is not clear from the published materials is why cognitive impairment and unrefreshing sleep were selected as the focus for the study. Expected outcome: A list of approved drugs that warrant further study for treating cognitive impairment and unrefreshing sleep in CFS.
Dane Cook (University of Wisconsin-Madison) will partner with Dr. Gordon Broderick and Drs. Kathy and Alan Light to link and validate information from earlier studies. Dr. Cook has conducted studies on brain imaging and post-exertional malaise in CFS. Dr. Broderick used his 2009 grant from the CFIDS Association to identify gene expression measures in a post-infectious mononucleosis cohort of CFS patients. Drs. Alan and Kathy Light used their 2009 Association grant to identify post-exercise gene expression changes in CFS, as distinguished from several control groups. All of these researchers presented results of their studies at the 2011 NIH State of the Knowledge Workshop. In this new grant, the investigators will examine functional brain imaging and analysis of blood markers after an exercise challenge. Systems analysis will map the links between reported symptoms, brain function, and gene expression of sensory, adrenergic and immune functions. Cook, Broderick and the Lights will attempt to link their findings in order to better understand post-exertional malaise. A potential weakness here is that it appears only a single exercise challenge will be used rather than the test-retest protocol used by the Pacific Fatigue Lab, but that may or may not impact the results of the study. Expected outcome: Cross-validation of novel blood and brain biomarkers in CFS which may identify contributing factors to post-exertional malaise.
Marvin Medow (Center for Hypotension, New York Medical College) was funded by the Association in 2009 to investigate the role of orthostatic intolerance in the cognitive dysfunction experienced by CFS patients. His research showed that CFS patients with postural tachycardia syndrome had decreased brain blood flow and greater cognitive impairment than healthy controls during an orthostatic challenge. This new grant will allow him to expand that earlier research, and test three interventions that increase blood flow (inhaled supplemental CO2 and two intravenous drugs). Those treatment interventions may help alleviate the cognitive impairment seen during the orthostatic challenge. Results will likely only be applicable to CFS patients who have POTS. Expected outcome: Identification of potential treatments to improve cognitive impairment that is aggravated by orthostatic intolerance.
Patrick McGowan (University of Toronto, Scarborough) will use SolveCFS BioBank samples to look for epigenetic changes related to the immune and HPA axis systems in CFS patients. Epigenetics is the study of changes in gene expression that are not the result of changes to the DNA sequence itself. Epigenetic changes, frequently the result of environmental factors such as nutrition or infections, cause genes to “behave” differently by activating or silencing their expression or by modifying the way a gene is transcribed. This study will observe the response of immune cells from CFS patients and healthy controls to a synthetic stress hormone, and then survey the genome looking for epigenetic changes in the immune cells. One potential weakness of the study is that it uses banked samples, rather than fresh samples with changes induced by a stressor like exercise testing. It would be wonderful to correlate an epigenetic survey with the gene expression changes detected in the Lights’ ion channel study. Still, this is one of the first systematic epigenetic studies in CFS. Expected outcome: Identifying epigenetic changes in CFS immune cells could identify biomarkers and treatment targets.
*Clarification – I served on the CFIDS Association Board of Directors from 2006 through 2011, but I did not participate in any stage of the review of grant applications submitted in response to the 2011 RFA.