“In response to interest generated by an earlier post on hot microglia as a therapeutic target, we have invited Professor Laura Airas, who presented her much talked about work on this topic at the recent AAN, to do a guest post. She has agreed to answer questions on the topic so please feel free to ask. This innovation in imaging has particular implications for progressive MS trials.”
Laura Airas, MD, PhD. Positron emission tomography (PET) holds promise for better treatment of progressive MS. Turku University Hospital, Turku, Finland
While there is increasing number of efficient therapies available for relapsing-remitting MS (RRMS), secondary and primary progressive MS (SPMS and PPMS) still remain the under-treated and under-investigated forms of the disease, and treatment of the progressive patients represent today the greatest unmet need in the field of MS. Consequently, many sufferers of progressive MS end up wheelchair-bound or bed-ridden, which not only causes huge impact on the quality of life, but also leads to enormous societal costs due to inability to work and dependence on carers.
We have been working with positron emission tomography (PET) imaging to see whether PET could provide more information about the underlying neuropathology in patients with secondary progressive MS than conventional MRI imaging can do. With PET imaging we can use radioligands that bind to activated microglial cells. This is an inflammatory cell type within the CNS, which gets activated in association with chronic degenerative diseases. Our latest work which was just recently presented at the American Academy of Neurology meeting in Philadelphia, USA, demonstrates that PET imaging allows us to visualize microglial cell activation in and around the MS lesions, and in areas of normal-appearing white matter, i.e. in areas that look normal in MRI. In other words, PET can give us more detailed information of the ongoing disease process in progressive MS, than MRI.
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| A patient in a PET scanner |
Our work indicates that PET holds promise as a research tool in understanding the central nervous system pathology of secondary progressive MS, and will also aid in recognizing new therapeutic targets. We have recently demonstrated using an animal model of progressive MS, that fingolimod-treatment led to reduced microglial activation, and this could be measured in vivo using PET. We believe that PET imaging could potentially be used as a biomarker in the development of novel treatments targeting progressive MS, and our findings will thus hopefully ultimately lead to better treatments for progressive MS.
Special interests of Dr. Airas include multiple sclerosis and pregnancy-related issues, mechanisms controlling lymphocyte homing into the CNS, development of novel drugs for MS, and advanced imaging techniques such as positron emission tomography (PET). She has been coordinating a Finnish nation-wide study looking at pregnancy-related alterations in MS immunopathology, and has numerous international collaborations in immunology and imaging fields. Dr. Airas also actively participates in clinical studies investigating new drugs to treat multiple sclerosis.
In addition to her scientific activities, she is responsible for neuroimmunological patients in the outpatient clinic of Turku University Hospital, and takes an active part in giving neuroimmunology-related education to fellow neurologists, other health care professionals, medical students and patients.
Dear Prof Aira,Are there any therapies that can impact hot microglia e.g. switch the process of? When does the hot microglia process start i.e. before the immune system gets into the brain or after?Many thanks
So should the MS Society et al be starting a fundraising drive to get some of these scanners here?
There are a large number of scanners in the UK already.
However makimg the tracers os a problem and few places do this
"We have recently demonstrated using an animal model of progressive MS, that fingolimod-treatment led to reduced microglial activation, and this could be measured in vivo using PET"http://multiple-sclerosis-research.blogspot.com/2013/12/gilenya-is-not-so-good-in-secondary.html?m=1Since Gilenya has shown that it does not prevent progression in EAE, I think microglia activation is a consequence of neurodegeneration not the cause.
Looks like you have been to the Tabloid school of reporting. Please tell me where in the post you cite does it mention that fingolimod reduced microglial activation and it was measured with PET. This certainly was not our work we have not used PET…yet.Gilenya is active early in EAE.Be careful how you interpret EAE studies. In a typical experiment fingolimod would be given to animals before the problem exists and this would lead to less microglial activation because the damaging immune response would not arrive in the CNS causing the activation of microglia.However turning off an aggressive microglial response after it is long established is what is needed.I suspect you are part wrong. microglial activation is indeed a consequence of some aspects of MS, but they may be be the cause of other aspects. These cells are good guys and bad guys it is all context dependent
Your post is entitled "Gilenya is not so good in secondary progressive EAE".So do you propose that Gilenya is going to have an effect on SPMS or PPMS?If your mouse model does not give any confidence about the potential effects in this form of MS in humans, why do the study? Why not just test aimlessly test any random drug to see if it has an effect on progressive MS?
"So do you propose that Gilenya is going to have an effect on SPMS or PPMS?"PPMS maybe. SPMS I don't know. It is Siphonimod that is being tested in SPMS not fingolimod"Why do the study". It is called an hypothesis. The effect in humans is not known we can make a prediction, but at the end of the day the human data is the important study. This is ongoing this will either help give validity to the model or not.Why not test aimlessly…at about £100,000 and 6 months an "aimless" test it is (a) not good value for money (b) a good use of time and (c) not good use of animals.
Why do you think it has a possible effect in PPMS and you are not sure about SPMS? Are these not fundamentally the same disease or do you subscribe to a different notion?
They are in my mind the same but the question waz about fingolimod it is not being tested currently in SPMS
Sphingosine-1 Phosphate -Receptor Targeting and Microglial Activation (FINGOPET)NCT02139696Looks like you will get an answer
Dear Professor,,Would addressing the issue of hot microglia slow or stop disease progession?
Yes..which drug shall we use. It has been shown that sodium channel blockers inhibits hot microglia, there are others Lamotrigine trial done…not good result as most people did not take the drug so not surprising what the result was. Minocycline was supposed to do this too However if Lamotrigine had worked then what? It has no patent life, no company support behind it, a bit like the Simvastatin….how do we get drug to you….the BPA
Maybe Prof G can write a quick grant to add PET imaging to the PROXIMUS study to get hot microglial imaging
Which radioligands do you use in your studies? Are they selective for "hot microglia"? How do they get in the brain? In other words, do they cross the "intact" blood-brain barrier?
The PET ligands for microglia get in the brain otherwise they would be useless. There are a few versions of ligand.
Thank you. Let me clarify my question: charged gadolinium MRI contrast agents get into the brain through breached BBB as a result of inflammation; no acute inflammation = no Gd enhancement, right? Is this also true for new PET imaging agents, or can then cross "normal" BBB?
Yes- No blood brain barrier leakage no gadolium however if a PET agent is of use then it should naturally cross into the brain irrespective of blood brain barrier leakage. A hydrophobic (non water soluble),lipophhilic (soluble in Fat) chemical should get to the brain. A number of agents have been made that dont cross the blood brain barrier.If you say made fingolimod as a PET agent you would see it lighting up the normal brain