Jeffrey I. Greenstein, M.D.
August 20, 2018
Dear Friend and Supporter
I am pleased to share with you some of the groundbreaking discoveries made at MSRI over the last few months due to your generous support.
- We have found that the CHEC peptides (compounds I discussed in previous updates) induce the production of a range of immunosuppressive cytokines (proteins that mediate de-activation of cells in the immune system). Cytokines can either increase or decrease immune cell activation. Because activation of immune cells is central to the development of autoimmune diseases like MS this finding is particularly relevant to the possible treatment of MS. When cytokines themselves are given as a therapy they often cause many adverse effects because they affect many tissues. Cytokines work on cells locally so a strategy to boost immune suppression just where it is needed using compounds such as CHEC makes a lot of sense.
- We are also authors on a paper newly accepted for publication which shows the same CHEC peptides can initiate the breakdown of protein aggregates (clumps) inside cells such as those in Alzheimer disease (and aggregates also occur in cells like oligodendrocytes – the myelin forming cells – when they are under immune attack). So our finding that protein clumps can be broken down has importance for many conditions including MS. We have also developed additional similar but new molecular structures in order to find which one is most effective. Our findings suggest that a wide range of possible diseases may be treated with these CHEC peptides because they not only directly protect cells from intrinsic damaging processes, but they also control the immune system by preventing its activation, thus providing a second path to prevent an inflammatory attack on tissues (i.e. autoimmunity). This unique type of therapy has considerable potential for treating MS in particular.
- We have also continued to study how the JC virus travels to the brain causing PML (Progressive Multifocal Leukoencephalopathy), a serious and potentially fatal infection which complicates a number of MS therapies including Tysabri, Tecfidera, Gilenya, Ocrevus and Lemtrada. This infection also complicates treatments for other autoimmune diseases, transplantation and chemotherapy. The JC virus lies dormant for the whole of our lives except in rare instances where it spreads to the brain. PML only occurs when there are mutations in the genes of the virus and when the immune system is depressed.
- The mystery has been to figure out how the JC virus gets to the brain, because there it has the potential to replicate and cause the tissue damage of Progressive Multifocal Leukoencephalopathy (PML). Thanks to your support, we have solved part of the mystery of how the JC virus gets to the brain by identifying the presence of live virus in immune cells. We also have shown that different circumstances such as exposure to therapeutic antibodies, affects the production of virus. If we identify that various stimuli such as antibody treatments induce mutations in the virus as well, then we will have solved one piece of the puzzle as to why PML occurs during antibody therapeutic treatments. In the long-term we would also like to investigate if antibody treatments also depress the immune system – the other half of the puzzle.
- By utilizing the PCR assay we (previously) developed to detect the JC viral DNA, we discovered the gene signature of the virus in the immune cells of everyone tested. So, the presence of the virus is not unique to MS. We found a decrease in the amount of viral DNA in immune cells as well as viral DNA in the fluid in which they are cultured when cells from those not on therapeutic antibodies are exposed to certain naturally occurring antibodies. This is a form of natural resistance to the JC virus in which viral proteins in immune cells are broken down. In contrast, there is an increase in viral DNA during a limited period of time when someone is on an antibody treatment, followed by a later reduction in the level of viral DNA to the normal level. These changes in viral DNA are not necessarily harmful (this also happens naturally with activation of a number of viruses which persist in our bodies). We are in the process of cloning and sequencing the viral DNA because if we find that at a particular time on treatment mutations in the JC virus occur (alterations in the genetic code of the virus), then this might correspond with a period of greater risk for PML.
- We have also established that the antibodies which stimulate the JC virus use a different mechanism than usual (antibodies usually bind their specific target with the front end of the molecule). Here the back end of the antibody molecule attaches to what are called Fc receptors on the surface of immune cells and transmit a signal which can activate the JC virus inside the immune cell.
I remain optimistic that with your continued support of our state-of-the-art scientific research at MSRI we will accomplish our goal to FIND, STOP and CURE MS. Unfortunately, state-of-the-art science is very expensive and your continued support will help us reach our goal to defeat this disease.
You can also help us in our endeavor to do cutting edge science to discover the cause of MS by increasing our level of recognition and support by adding the name and contact information of family, friends and colleagues on the enclosed card or directly on our website (www.msresearchinstitute.org).
Jeffrey Greenstein, MD
PS. We will have a Fundraiser Concert on 11/3/18 so please save the date. Wonderful internationally acclaimed artists will perform. Details are to follow.
We still have some available wall tile spaces, so if you would like to purchase one please look at the enclosed instructions.