The NIH on ME/CFS in 2012: Pt II – the Studies

Getting the preliminary data is just the beginning, though.  With grant success rates at less than 20%, grants are hard to come by.  The NIH estimates that grant success rates of about 30% are about right; anything lower than that suggests the NIH may be missing  significant breakthroughs. First time grant success rates in the mid-late 2000s, for ME/CFS, however, were only around 8% . Nevertheless, the money, when they can get it, is so good that’s it’s well worth the effort.  The CFIDS Association, for instance, has been able to parley their recent small grant packages into millions of dollars of NIH funded studies.

Let’s take a look at what kinds of studies the NIH is funding in ME/CFS right now.  From an endogenous retrovirus study to three blood vessel studies to a completely different view of the immune system, to a study that is explicitly trying to break CFS apart, the NIH is funding some fascinating studies, which could, if they have positive results, make a big difference in ME/CFS.  Several important studies are ending this year. ( See studies whose titles are in red ).

The NIH is funding some good stuff but it could all end pretty quickly. Remember the ‘donut hole’ in pharmaceutical coverage in the Bush plan?  NIH neglect has left their CFS research program with a donut hole of its own that its about to hit. Unless the NIH gets its act together even this low level of research funding is unsustainable.

Check out a sobering assessment of the future of the NIH’s CFS research program in

• Pt III of the NIH on ME/CFS on 2012 series – NIH Neglect Imperils ME/CFS Research Program (coming soon)

IMMUNE SYSTEM

Capturing ME/CFS in All its Glory? The Good Day/Bad Day Study

• Title – Immunologic Mechanisms, Biomarkers, and Subsets in Chronic Fatigue Syndrome (CFS)
• Investigator  – Dr. Mary Fletcher at the Univ of Miami
• Duration – 2006-2012
• Money Spent Thus Far – $1,750,000

Description – Dr. Fletcher’s ‘Good Day/Bad Day’ study will determine if immune system functioning differs on a patients’ ‘good,’ ‘bad’ and ‘normal’ days. Whether immune and other studies are missing important information because they happen to be hitting some patients on their ‘good’ days is a surprisingly important question. Study findings are often more significant when patients are stressed with exercise or other stressors, suggesting that it could be important to catch patients on bad days. If this question is answered positively, it could change how researchers do studies.

The study will also determine if symptom severity is associated with reductions in the immune system’s ability to fight off invaders.  It’s basically asking if you worse because your natural killer cells have tanked allow your  herpesviruses to run rampant.  That sounds like a good theory and it’ll be fascinating to see what this study turns up. They also hope to find biomarkers and specific targets for immune-modulator therapy.

Results Thus Far – the Fletcher study has already produced a panoply of results  with neuropeptide Y providing a link between the autonomic nervous and immune systems and a potential biomarker (dipeptidyl peptidase/CD 26) popping up.  The biomarker evidence appeared strong; it showed up in a large study (n=406). Reduced levels of DPPIV/CD 26 suggested that chronic lymphocyte activation, possibly in response to a chronic infection, was present.  Reduced DPPIV/CD 26 levels could result in reduced T helper and other immune cell activation. With a main focus of the grant – the Good Day/Bad Day study – yet to be published, the study is due to wrap up late this year.

An Endogenous Retrovirus Researchers Want to Find: the HERV K18 Huber Study Nears Completion Description 

• Title – HERV-K18 AS A RISK FACTOR FOR CFIDS
• Researcher – Dr. Brigette Huber at Tufts University, Boston
• Duration – 2007-2012
• Money spent thus far – $1,500,000

Description – XMRV is mostly gone in the research world’s eyes, but EBV, the most studied pathogen in ME/CFS prior to the XMRV surge, lives on. (One wonders where we would be if a tenth of the resources devoted to XMRV had been devoted to EBV.) The immune signature the Fletcher study is finding suggests reactivated latent herpesviruses (i.e. EBV and others) are present. Glaser is pursuing his theory of EBV-triggered immune dysfunction and sickness behavior, and here Dr. Huber is looking for evidence that an endogenous retrovirus called HERV-K18 has been activated by, yes, EBV in CFS patients.

Most endogenous retroviruses in the human genome are broken up, inactive bits of old viruses – which can sometimes look like live viruses – hence researchers disappointment when they accidentally pick one up in their studies.  HERV K18 is different – researchers know it can become activated in the human body and cause problems). That’s not all – she also has evidence that HERV-K18 then activates a ‘superantigen’ which has the potential to send ME/CFS immune systems amok (perhaps explaining why portions of it appear, in some studies, to be ‘burnt out’). This is a big, big study – 400 CFS patients – one of the largest ever undertaken in ME/CFS.  Dr. Huber is also working with Dr. Renee Taylor – who is working on a major study of her own.

The exciting thing is that Dr. Huber’s long five year study is due to end this year.  Dr. Huber has been silent throughout this project; there have been no conference appearances and no papers published. We should be hearing soon how this intriguing study has ended up.

Bad Systems Wiring: Cutting Edge Work From Dr. Klimas

•  Title – STUDY OF CHRONIC FATIGUE SYNDROME USING COMPREHENSIVE MOLECULAR PROFILING WITH NE
•  Investigator  – Dr. Nancy Klimas of Nova Southeastern University
•  Duration – 2010-2014
•  Money Spent Thus Far – $1,000,000

Description – Dr. Klimas’s focus on ‘regulatory elements’ and multi-systemic interactions in this study is hand in glove with the NIH’s view of ME/CFS.  The first sentence of her hypothesis reveals how unusual this study is: We hypothesize that CFS results not only from component failure but perhaps more importantly from a significant deterioration of regulatory function linking these components and her study will use exercise to test what she calls ‘regulatory fitness’.  The plan is to use a stressor (exercise) to activate the stress response and then monitor what it does to the nervous, endocrine and immune systems.

In this complex study, Dr. Klimas will use molecular profiling to assess the status of these systems, describe the interactions between them, and highlight areas where the ‘wiring’ has gone wrong, thus imperiling the homeostatic balance in the body. She’ll then do computer simulations of this data to attempt to produce treatment courses that “redirect the system as a whole to a normal resting state” (!). This is the type of innovative, cutting edge stuff the NIH loves to fund and it has been well-funded, chewing up about $1,000,000 in two years. The project started in 2010 and is slated to end in 2014.

Glaser Finally Gets His EBV Study (By bypassing CFS)

•   Title – STRESS EFFECTS ON VIRUS PROTEIN INDUCED INFLAMMATION AND SICKNESS BEHAVIOR
•  Investigator  – Ronald Glaser at Ohio State University
•  Duration – 2010-2015
•   Institute(s) Funding –  National Institute of Allergy and Infectious Diseases
•   Money Spent Thus Far – $1,300,000

Description – After years of trying, Ronald Glaser finally got his (CFS) EBV study. All he had to do was re-focus it on other disorders and take it to another review panel.  A former CFSAC member, Dr. Glaser took every opportunity to vent his spleen at the craziness of having review panels loaded with pain and dental researchers review immune grants. Once he got his application over to a suitable review panel, it flew through. In this five year study, Glaser will try to validate a key aspect of his (and Dr. Lerner’s) theory that a simmering, non-replicating EBV infection, in combination with stress, can produce a protein (dUTPase) that causes immune upregulation and the symptoms of ‘sickness behavior’ (fatigue, pain, etc.) that pervade ME/CFS. No CFS patients will be used in this study, but at the Ottawa Conference an enthusiastic Dr. Lerner presented preliminary findings indicating that this protein is significantly increased in ME/CFS patients and that they are going back to the NIH to attempt to get more funding.

A VERY DIFFERENT IMMUNE APPROACH: MAST CELLS AND ME/CFS

•  Title – BRAIN MAST CELLS AND CHRONIC FATIGUE SYNDROME
•  Investigator – Theoharis Theoharides at Tufts University
•   Duration – 2010-2014
•  Institute –  National Institute of Neurological Disorders (NINDS)
•   Money Spent Thus Far – $700,000

Theoharides is a name that is less known to the ME/CFS community, but he comes with a fascinating resume and an intriguing theory.  A massively published researcher (over 300 publications), Theoharides has been digging into mast cells for over 30 years and in 2006 he finally made his way to ME/CFS when he won one of the seven Neuroimmune RFA grants.  Nobody else has come within a stone’s throw of mast cells in CFS, but Theoharides reports mast cell/mast cell mediator problems have been found in every disorder allied with it, as well as autism.

In two interesting twists, Theoharides found that the mitochondria, always a question mark in ME/CFS, regulate mast cell degranulation and that mercury – another possible factor (which has received no study at all) –  triggers mast cells to release factors that could disrupt the blood-brain barrier and trigger brain inflammation. HPA-axis hormones can also activate factors that increase blood vessel permeability and increased permeability of the blood brain barrier.  In this study, Theoharides will test his theory that stress causes brain mast cells to produce fatigue producing molecules.

There are no CFS patients in this study – this is a mouse study – but if the Theoharides theory proves out, researchers will have a new theory of fatigue to explore and new parameters to look at. Theoharides believes flavonoid combinations (luteolin/quercetin/olive kernel oil) may be able to blunt this kind of fatigue and he is exploring that idea as well in this study. Theoharides has used two ‘CFS’ grants to support his theory that mast cells play a key role in neuro-inflammation but has yet to spend a nickel directly on a single CFS patient.  Hopefully his latest research findings will lead him to test his theories on some ME/CFS patients.

Study in Limbo – the Big Mikovits/WPI (XMRV?) Pathophysiology Study

•  Title – NEW STRATEGIES TO DECIPHER THE PATHOPHYSIOLOGY OF CHRONIC FATIGUE SYNDROME
• Investigator  – Judy Anne Mikovits of the Whittemore Peterson Institute
• Duration – 2009-2014
• Institute(s) Funding – National Institute of Allergy and Infectious Diseases
•  Money Spent Thus Far – $1,000,000

The Mikovits/WPI XMRV Lipkin study issue was resolved successfully but with XMRV on the ropes, this study now looks a heck of a lot more enticing. Dr. Mikovits proposed that multiple viruses interact with a susceptible genetic background to cause ME/CFS. This big study was/is focused on elucidating novel viruses (XMRV presumably), characterizing genotypes that give the virus a foothold, determine holes in the IFN-a pathway, validate Kerr’s 88 gene expression profiles and characterize the mantle cell lymphoma subset in ME/CFS to boot.

Results Thus Far – One paper suggested a unique immune signature present in people infected with XMRV.  Where this study stands now with the XMRV finding in disarray and Dr. Mikovits departure from the WPI is unclear.

NERVOUS SYSTEM

If one area sticks out in the package of research it’s a focus on the blood vessels and nitric oxide.  The Stewart POTS study, the Friedman orthostatic intolerance study, the Biaggioni autonomic nervous system studies, the Natelson brain study, and the Theoharides mast cell (immune) study are all focused on blood vessels and blood flows.  A subfocus on nitric oxide levels in the blood vessels in no fewer than three of the studies demonstrates how hot a topic that is. (In contrast to Pall’s theory of increased nitric oxide production, these studies posit that nitric oxide production is reduced.) Three ongoing POTS studies suggest the NIH can throw resources at a problem they get interested in.

All in the Blood Vessels? Biaggioni Proposes Negative Feedback System in Blood Vessels Causes ME/CFS

•  Title – AUTONOMIC NERVOUS SYSTEM IN CHRONIC FATIGUE SYNDROME
•  Investigator /Institution – Italo Biaggioni at Vanderbilit
•  Duration – 2006-2012
•  Money Spent Thus Far – $1,500,000

Description – Dr. Biaggioni posits that a negative feedback loop is at work in the blood vessels of people with ME/CFS and/or POTS. Specifically, he proposes that reduced nitric oxide production in the blood vessels results in increased sympathetic nervous system activity and vice versa; increased SNS activity results in reduced NO production. He will also determine if increased inflammation is associated with increased SNS activity. If he’s correct, then simply reducing the chronic sympathetic nervous system activity could result in a whole host of effects including reduced cardiovascular problems, blood volume and inflammation and reduced overall symptoms.

Results Thus Far – Several papers have come out of this long study. Biaggioni has documented angiotensin abnormalities in some POTS patients and found that low doses of the beta blocker propranolol significantly reduced the racing heartbeats and symptoms found in POTS patients, while high doses may make some POTS patients worse. The big news we’re waiting for is whether Biaggioni’s theory that reduced NO levels are at heart of this disorder – causing sympathetic nervous system over-activation,  low blood volume, cardiovascular problems, POTS, etc. is correct.

This study is due to end this year and we should be hearing something soon.

Ten Years and Almost 4 Million Dollars Later A ‘Study’ Ends

•  Title – ORTHOSTATIC INTOLERANCE IN CFS
• Investigator – Roy Freeman at Beth Israel Deaconess
•  Duration – Ten years, on and off, to 2012
•  Money Spent Thus Far – $3,900,000

Description – Dr. Roy Freeman also believes nitric oxide production in the blood vessels holds a key to CFS and his study fits glove in hand with the Biaggioni one. In this novel study Freeman will alternately increase and decrease both NO levels and sympathetic nervous functioning and examine the effect that has on autonomic nervous functioning and symptoms in CFS patients with postural tachycardia syndrome (POTS). Dr. Freeman believes two kinds of POTS patients are present in the CFS community and this study will elucidate them.  Recall that Biaggioni suggested that reducing sympathetic nervous system functioning could restore proper blood volume levels, cardiovascular functioning, etc.

Results – Dr. Freeman has been studying autonomic nervous dysfunction in CFS for over ten years and has received almost $4 million in funding, but except for several early papers has published little. This long ‘study’ – which originated in a grant that was extended year after year – is due to end in June of this year, though, and hopefully we will see a series of papers coming out.

Nitric Oxide on the Fence: Too Little or Too Much (or Both) in ME/CFS

• Title – VASCULAR DYSFUNCTION IN CFS
•  Investigator – Julian Stewart at New York Medical College
•  Duration – 2008-2013
• Money Spent – unsure ($350,000 in 2011)

Description – Stewart also believes nitric oxide lays at the heart of both POTS and CFS. This is a POTS/CFS study that thankfully looks at ME/CFS patients with and without POTS. Like the other researchers, Stewart believes POTS patients may be producing too little NO, but he also believes a subset of CFS patients without POTS are producing (get this) too much rather too little NO.  Stating that this study will explore the ‘subclinical microvascular ‘abnormalities’ in CFS patients without POTS, this study will be the first to directly test at least part of Pall’s theory that too much NO production is causing increased oxidative (nitrosative) stress.

Taking a tack from several MERUK studies, it will also look at acetylcholine levels. This study also includes a clinical trial that will determine whether the A-11 receptor blocker losartan can increase blood flows and blood volume in patients with low NO levels. Another section of this quite large study will determine if subcutaneous octreotide can reduce blood pooling and increase blood flows in non-POTS patients with CFS.  This drug is used, among other things, in combination with Midrodrine to reduce vasodilation in kidney patients.

Results Thus Far – Stewart has been pumping out papers on orthostatic intolerance with over 20 co-authored in 2011 alone. A 2011 study found that ascorbate increased blood flows in low-flow POTS patients. Another 2011 study found strangely activated cerebral blood flows and a variety of other abnormalities during tilt, and another found POTS patients’ cognitive abilities declining as they were tilted up. This big study will end next year.

Finally Splitting ME/CFS Up? the Natelson Brain Study

• Title – NEUROPATHOLOGIC ABNORMALITIES DEFINE A SUBGROUP OF PATIENTS WITH CFS
•  Investigator  – Benjamin Natelson at Beth Israel Medical Center
•  Duration – 2011-2013
• Money Spent Thus Far – $360,000

Description – Benjamin Natelson has looked at many different areas of ME/CFS over the years but none has been more interesting or unusual than his depression studies. One of the more intriguing findings of ME/CFS research over the past ten years has been Natelson’s findings that cognitive problems, cerebrospinal fluid problems, and abnormal brain blood flows and lactate levels are more present in ME/CFS patients who are not depressedthan in patients who are depressed.

“…there has emerged strong preliminary evidence that supports the existence of a subgroup of CFS patients whose illness appears to be due to specific biological abnormalities in the brain” 

Natelson is not talking about a change of emphasis; he believes people with ME/CFS without depression suffer from a different illness than people with ME/CFS with depression and that he has ‘neurobiological’ evidence of that. This is not a small group; study estimates of the rate of depression present in ME/CFS ranges from 30-50% – this could be a big deal. Now Natelson is been given a grand opportunity to validate his findings by looking at all these factors in one study. This may be the best chance yet to subset the ME/CFS community and create more coherent sample groups for studies – leading to more significant results, more positive studies and ultimately more research funding. This study ends in 2013.

Tired Body, Tired Mind: How Fatigue Affects ‘Everything’

•  Title – MOLECULAR RECEPTORS ON GROUP III-IV SENSORY NEURONS DETECTING MUSCLE METABOLITES
•  Investigator – Alan Light/ Univ of Utah
•   Duration – 2012-14
•   Money Spent Thus Far – $500,000

Description – This is the kind of study the NIH loves. This isn’t about CFS; it’s basic science aimed at uncovering the cause of excessive fatigue not just in CFS but across the board in other ‘excessively’ fatiguing disorders such as heart failure and chronic obstructive pulmonary disorder (COPD).   The Lights are doing for fatigue what they and others have done for pain – determining on a molecular basis how fatigue is generated and then how it affects key systems in the body and brain.

One sentence in the description describes their work perfectly.

“The results of these experiments will provide the basic science background for the concept of fatigue as an integrated system with powerful influences on the cardiovascular/autonomic system, the sensory-perceptual experience of fatigue, and motor system inhibition.”

This is fascinating stuff. The Light’s believe they will be able to uncover the molecular factors that trigger abnormal sympathetic nervous system activity, tell the motor system of the brain to reduce contraction of the muscles and activate the sensory areas of the brain to produce the ‘overwhelming sensation of fatigue’. This is an integrated attempt to explain not only why a person feels fatigue but why they have so much difficulty exercising (contracting their muscles).

They hope their efforts will lead “to rational, targeted effective treatments for the excessive fatigue experienced by heart failure patients, patients with COPD, and other patients suffering from prolonged, unexplained fatigue.” This was a quickie study for the NIH – just two years – it’s due to end in 2014.

The NIH Backs the Lights – Big Time

•  Title – POST-EXERCISE ION CHANNEL GENE EXPRESSION BIOMARKERS IN CFS
•  Investigator  – Kathleen Light at the University of Utah
•  Duration – 2011-2014
• Money Spent Thus Far – $336,000

Description – With their gene expression studies focusing on genes known to act up when our muscles get tired, the Lights have basically created a field of their own and it appears that the NIH appreciates their creativity and persistence. This study is a major expansion of their last grant which looked at the gene expression of receptors known to become activated during exercise.  This is the study that produced the captivating charts of activated nervous system and immune receptors after exercise.

This grant just about doubles their study size (up to 140 patients!), tacks on a full genomic array (instead of selected genes), takes a deeper look at a collection of genes of special interest, and adds another control group – prostate cancer patients with fatigue.  Like the Natelson study, this is a validation study plus; its first goal will be to validate the results of the old study with new patients and then hopefully expand on it.

With its attempt to define ‘dysregulated pathways’ in ME/CFS this study also fits right in with the NIH’s emphasis on ‘dysregulation’ and the Lights believe these studies will provide clues for new treatment options.  This is the kind of large, complex, expensive study that the NIH probably does better than just about anyone else.

Clinical Trials

Stress (and Immune System) Management Over the Phone

•  Title – PATIENT-PARTNER STRESS MANAGEMENT EFFECTS ON CFS SYMPTOMS NEUROIMMUNE PROCESS
•  Investigator – Michael Antoni at the University of Miami
•  Duration – 2010-2015
• Money Spent Thus Far – $1,000,000

Description – A blend of stress reduction and biology, Antoni’s five year study will examine the effectiveness of a telephone based cognitive behavioral stress management program in decreasing pro-inflammatory cytokine levels,  altering the cortisol response and decreasing symptoms.  They will use stress management techniques such as relaxation and cognitive, behavioral and interpersonal skills training.

This stress reduction study is unique in that it will determine if these stress reduction therapies are helping to rebalance the immune system and HPA axis and reduce symptoms.  Antoni  is well acquainted with immune system functioning  as he has co-authored several of the Fletcher/Klimas immune studies of the past five years.  His first study from the 2006 RFA found that his blend of cognitive behavioral stress management resulted in reduced symptoms, reduced stress and increased quality of life.

The NIH was apparently pleased with his work as they approved a second five year study using partners and taking a look at the immune system. Results thus Far –  none.

An Inexpensive Home Based System of Self Management Debuts

•  Title – EFFICACY OF HOME-BASED SELF-MANAGEMENT FOR CHRONIC FATIGUE
•   Investigator /Institution – Dr. Fred Friedberg/ Warren Stress Management
• Duration – 2007-2013
•  Money Spent Thus Far – $420,000

Dr. Friedberg has been funded since 2007 but this is the first time this project has received real money. Relative to the other studies, it’s not particularly expensive and it could result in the production of an inexpensive course of self-management. Dr. Friedberg certainly knows his subject since, unlike other behavioral therapists in the CFS field, he actually has the disorder and has used these techniques himself. Nobody is claiming a cure but, if Dr. Friedberg succeeds in reducing symptoms somewhat by reducing inflammatory factors through relaxation and other techniques  – and in doing so create a cheap program ($20) that anyone can use – the study may be  worth it.

The Viagra Study

•  Title – CLINICAL TRIAL: USE OF SILDENAFIL (VIAGRA) TO ALTER FATIGUE
•  Investigator – Theodore Friedman at UCLA
• Duration – Through 2012
• Money Spent Thus Far – ???

Description– At first blush, Viagra sounds like an odd drug for an ME/CFS study, but the same processes Viagra uses to assist the ‘little brain’ in its functioning should be able to affect the ‘big brain’ as well. Friedman’s double-blinded, placebo controlled study to determine if Viagra increases brain blood flows and reduces symptoms is the only non-behavioral clinical trial the NIH is funding in ME/CFS.  Friedman, working out of Los Angeles, was reportedly having trouble recruiting patients earlier in the study. This study is due to end in June 2012.

XMRV

Besides the money NIH researchers poured into XMRV out of their discretionary funds, the NIH funded quite a few XMRV studies.                

•  The Lipkin Study (MULIT-CENTER BLINDED ANALYSIS OF XMRV/MLV IN CHRONIC FATIGUE SYNDROME) should finish up in a few months.  
• The Hanson Study (THE RELATIONSHIP OF XMRV TO FUNCTIONAL STATUS AND CO-INFECTIONS IN CHRONIC FATIGUE SYNDROME)  was slated to run through 2015 but with Hanson unable to find XMRV and her finding that the MLVs she did pick up appeared to be due to contamination this study is likely over.  ($700,000 spent)
•  The Wolin Study  (Recruitment of Host Noncoding RNAs by XMRV) is slated to run through 2014. ($251,000 spent).
• The Pathak Study (REPLICATION AND PATHOGENIC POTENTIAL OF XMRV IN HUMANS) provided genetic evidence that XMRV was likely a contaminant.    
• Sandra Ruscetti’s study (MOLECULAR BASIS FOR THE PATHOGENESIS OF MURINE RETROVIRUSES) funded by the NCI  
• Monica Roth’s study (INTEGRATION OF MURINE RETROVIRAL VECTORS) has spent $293,000 thus far.          
• Graham Simmon’s study (CHARACTERIZATION OF XMRV AND OTHER MLV-RELATED VIRUS DETECTION FOR SCREENING OF BLOOD) has spent $261,000 thus far.

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