Good luck with the presentation, Prof G! Honestly, as someone with MS who is just fighting to survive each day, I don't think this stuff effects me personally. It would have to lead to a treatment that undoes the damage already done to me by MS and the NHS. And be available in my lifetime. And to someone in my socioeconomic position. I'm not optimistic 🤕
Might autoimmunity be triggered by a response to a virus?
So far we have lots of autoimmune diseases. No-one ever really bothers to find out what triggered them since, once triggered, they seem to carry on by themselves after the trigger is removed. At least as far as anyone can tell...
With MS there's a possibility that cycles of EBV flaring and cycles of MS flaring are simultaneous and could even be causal. Certainly, as you mention, Atara are looking at "what happens if we find a way to break this potentially causal link?". Similarly, a few more intrepid (desperate?) MS patients are finding ways to routinely obtain drugs such as Tenofovir which may reduce EBV levels and potentially lead to halt in progression and even possibly reversal of some damage.
Whilst this would never be able to repair full ataxia, never say never...
https://www.bbc.com/news/science-environment-65689580 - "The act of walking trains their muscles and has restored a degree of movement when the system is turned off, suggesting that damaged nerves may be regrowing."
May 25, 2023·edited May 25, 2023Liked by Gavin Giovannoni
A billion dollar question - how much would it cost the pharma companies in revenues if it is proven MS is due to a virus rather than an autoimmune disease?
Not a conspiracy theory, but sure does mimic one or call this a pure greed play, the anti-viral drugs would be inexpensive vs the DMT'S.
I say you're dead on, big Pharma MS DMT's revenue per year in the USA is Billions of dollars, thus losing billions overnight could be problematic if anti-viral theory is proven to be the holly grail or slows MS progression.
I've read about MS EBV studies 20+ years ago or MS patients with AIDS resulted in MS remission via anti-virals. shows promise, but.
These studies didn't continue, perhaps anti-virals didn't move the profit needle much vs immune system manipulation drugs.
The research game is a repeat and redo industry to continue the big monies to universities, PHD candidates and the PHD'S, next, and repeat.
Appears big Pharma and Universities chose to skip over the anti-viral MS research decades ago vs the developing novel immuno drugs resulting in billions of profits. These DMT's are bandaid drugs one cannot stop in theory or risk damaging rebound effect, these drugs generate big profits every month, q 6 months or one big pay day with expensive Lemtrada or HSCT treatment in a foreign land or a third dose of Lemtrada.
HSCT is another head scratcher. Why doesn't the good ole USA allow HSCT already?
People say we need more research which is a ruse, credible decade old Stem cell clinics practicin in the USA and the generic chemo drugs are inexpensive.
Only the wealthy or the lucky few included in HSCT studies in the USA. Again, this is where universities will get their cut before MS patients are helped, next, repeat saying we're almost to the end point or trials to start soon, ya thanks.
I deleted first post because system wouldn't allow editing.
I haven't read anything about Covid patient, however Covid patients were given a short course of anti-virals x 5 days, AIDs patients take anti-virals long term every day.
May 31, 2023·edited May 31, 2023Liked by Gavin Giovannoni
Dear Prof. G,
you are mentioning that the cervical lymph nodes are of special interest in reducing EBV/ MS interactions. As Ofatumumab s.c. injected in the lower extremities seams to be distrubuted also by the lymphatic vessels - wouldn't it be interesting to inject it in the buccal region s.c. so it is drained via the cervical lymph nodes? Furthermore, if EBV clearing of cervical nodes is of special interest - wouldn't it be intersting to explore CD19-Ab s.c. in the buccal and/or nuchal regions s.c. to reduce the load of EBV infected B-cells and plasma cells from the cervical lymph nodes?
We think the cervical lymph nodes are important because they are enlarged in pwMS and in one case of PPMS there was evidence of lytic EBV infection. I am not sure if buccal ofatumumab would work as it would likely go via the superficial sublingual and submandibular nodes and not the deep nodes. Similarly, nuchal injections will go via the superficial not deep nodes.
You are completely right, that it would primarily drain into the superficial sublingual and submandibular nodes. Those drain into the Levels IB and II (buccal) and Levels II and V (occipital/nuchal), which drain (at least partially) into the deeper Levels (Table 1, in (1)).
As the s.c. antibodies reach the venous system in humans (Phase 2 Studies), and patients report symptoms after a few hours after first application s.c. (in correspondence to the time the lymphatic system needs to transport the Ab from the injection side through various lymph nodes to the venous angle), I was wondering if enough Ab would reach the relevant lymph nodes.
Together with the observation in mice, that s.c. Ofatumumab favors lymph nodes (2), the presentation pattern of cervical lymphadenopathy in EBV (3) and the findings regarding EBV in MS (4-5), I was wondering, it might be really interesting to target localized applications in a manner of personalized medicine. Based on (PET?)-MRI data of the affected patiens cervical lymph nodes, together with an ENT colleague and maybe patient mapped lymphdrainage of different possible application sides, a targeted EBV purge of the affected cervical lymph nodes might be possible?
With less effort, a sonographic study pre and post s.c. application could show signs of hyperperfusion of the LN due to inflammation after cell-lysis in those nodes?
In context of the EBV+ nodes in MS (4-5) and a possible role of the glymphatic system it might be worth a shot.
And thank you again :)
References.
1) Pathways for Cervical (lymphatic) Metastasis in Malignant
Prof G, you are the one to lead this discussion! Below is how I've been describing the options to treat EBV. You did not include option 3, restor immune tolerance to MBP. Does this not seem feasible to you?
Treating Epstein Barr (EBV) as a cause of MS is planned or currently underway in multiple trials. The approaches can be grouped into four categories.
1) Diminishing the viral load of EBV with antiviral or antiretroviral treatments with currently available drugs, which is the subject of this profile. None of these currently approved drugs are optimal for EBV so the question is, can they fill a stop-gap role while more effective therapies are designed specifically for EBV? Also, May 2023 the Immunic trial of Vidofludimus Calcium reported a strong antiviral effect against EBV.
2) Selectively removing EBV-infected B cells with modified T cells (e.g. ATA188 by Atara; Imotope peptide by Imcyse).
3) Rather than directly remove EBV as in the first two approaches, restore regulatory and inflammatory T-cell balance, to induce immune tolerance to MBP. There are currently 10 trials to correct intolerance to myelin basic protein due to molecular mimicry caused by EBV (e.g. ANK-700 peptide, LPX-TI641 activates the Tim3 and Tim4 receptors, to boost expansion of Tregs, and multiple mRNA therapeutic vaccines).
4) Combing one of the first 3 options with remyelination or neurodegenerative repair therapies, some of which are already showing positive results in trials (e.g. MSC stem cells, CNM-Au8 Nanocrystalline Gold, NVG-291 and others)
I’m sincerely hoping that your approach is taken seriously and there will be funding. I admit what immediately came to mind was what Stephen voiced. Stick to it!! Best regards, Prof G with your presentation.
This week's article was very hard to follow for a ley person like me. A single silver bullet has long since been ruled out for MS leaving the collusion of one or more factors being likely.
* Is EBV a catalyst? Some have suggested covid has triggered MS too? Both viral. Why does EBV activate in some people to cause IM? Why did Covid-19 kill a small number of people who fell outside the high-risk groups?
* And what of the role of stress testing? By putting the body under undue load e.g. childbirth, stroke, serious injury appears to make the body vulnerable to attack.
As you say, big data may provide the answers and join the threads together because they seem disparate at the moment.
Good luck with the presentation, Prof G! Honestly, as someone with MS who is just fighting to survive each day, I don't think this stuff effects me personally. It would have to lead to a treatment that undoes the damage already done to me by MS and the NHS. And be available in my lifetime. And to someone in my socioeconomic position. I'm not optimistic 🤕
Is there any possibility of doing radiolabled acyclovir imaging (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125728/) to see if EBV lytic activity corresponds to MS lesion location or disease activity?
Maybe. I will ask a the question to a colleague of mine who works with PET.
Might autoimmunity be triggered by a response to a virus?
So far we have lots of autoimmune diseases. No-one ever really bothers to find out what triggered them since, once triggered, they seem to carry on by themselves after the trigger is removed. At least as far as anyone can tell...
With MS there's a possibility that cycles of EBV flaring and cycles of MS flaring are simultaneous and could even be causal. Certainly, as you mention, Atara are looking at "what happens if we find a way to break this potentially causal link?". Similarly, a few more intrepid (desperate?) MS patients are finding ways to routinely obtain drugs such as Tenofovir which may reduce EBV levels and potentially lead to halt in progression and even possibly reversal of some damage.
Whilst this would never be able to repair full ataxia, never say never...
https://www.bbc.com/news/science-environment-65689580 - "The act of walking trains their muscles and has restored a degree of movement when the system is turned off, suggesting that damaged nerves may be regrowing."
A billion dollar question - how much would it cost the pharma companies in revenues if it is proven MS is due to a virus rather than an autoimmune disease?
Stephen, that is immediately what I thought as well, I am loathe to admit. However I selfishly hope the viral issue is vigorously pursued.
Not a conspiracy theory, but sure does mimic one or call this a pure greed play, the anti-viral drugs would be inexpensive vs the DMT'S.
I say you're dead on, big Pharma MS DMT's revenue per year in the USA is Billions of dollars, thus losing billions overnight could be problematic if anti-viral theory is proven to be the holly grail or slows MS progression.
I've read about MS EBV studies 20+ years ago or MS patients with AIDS resulted in MS remission via anti-virals. shows promise, but.
These studies didn't continue, perhaps anti-virals didn't move the profit needle much vs immune system manipulation drugs.
The research game is a repeat and redo industry to continue the big monies to universities, PHD candidates and the PHD'S, next, and repeat.
Appears big Pharma and Universities chose to skip over the anti-viral MS research decades ago vs the developing novel immuno drugs resulting in billions of profits. These DMT's are bandaid drugs one cannot stop in theory or risk damaging rebound effect, these drugs generate big profits every month, q 6 months or one big pay day with expensive Lemtrada or HSCT treatment in a foreign land or a third dose of Lemtrada.
HSCT is another head scratcher. Why doesn't the good ole USA allow HSCT already?
People say we need more research which is a ruse, credible decade old Stem cell clinics practicin in the USA and the generic chemo drugs are inexpensive.
Only the wealthy or the lucky few included in HSCT studies in the USA. Again, this is where universities will get their cut before MS patients are helped, next, repeat saying we're almost to the end point or trials to start soon, ya thanks.
I deleted first post because system wouldn't allow editing.
Interesting about the AIDs patients on anti virals having remission. Didn’t the same thing happen with Covid patients too?
I haven't read anything about Covid patient, however Covid patients were given a short course of anti-virals x 5 days, AIDs patients take anti-virals long term every day.
Dear Prof. G,
you are mentioning that the cervical lymph nodes are of special interest in reducing EBV/ MS interactions. As Ofatumumab s.c. injected in the lower extremities seams to be distrubuted also by the lymphatic vessels - wouldn't it be interesting to inject it in the buccal region s.c. so it is drained via the cervical lymph nodes? Furthermore, if EBV clearing of cervical nodes is of special interest - wouldn't it be intersting to explore CD19-Ab s.c. in the buccal and/or nuchal regions s.c. to reduce the load of EBV infected B-cells and plasma cells from the cervical lymph nodes?
What are your thoughts?
Yours sincerely,
Paul
We think the cervical lymph nodes are important because they are enlarged in pwMS and in one case of PPMS there was evidence of lytic EBV infection. I am not sure if buccal ofatumumab would work as it would likely go via the superficial sublingual and submandibular nodes and not the deep nodes. Similarly, nuchal injections will go via the superficial not deep nodes.
A nice idea; thanks for sharing.
Dear Pro. G,
Thank you for your answer :).
You are completely right, that it would primarily drain into the superficial sublingual and submandibular nodes. Those drain into the Levels IB and II (buccal) and Levels II and V (occipital/nuchal), which drain (at least partially) into the deeper Levels (Table 1, in (1)).
As the s.c. antibodies reach the venous system in humans (Phase 2 Studies), and patients report symptoms after a few hours after first application s.c. (in correspondence to the time the lymphatic system needs to transport the Ab from the injection side through various lymph nodes to the venous angle), I was wondering if enough Ab would reach the relevant lymph nodes.
Together with the observation in mice, that s.c. Ofatumumab favors lymph nodes (2), the presentation pattern of cervical lymphadenopathy in EBV (3) and the findings regarding EBV in MS (4-5), I was wondering, it might be really interesting to target localized applications in a manner of personalized medicine. Based on (PET?)-MRI data of the affected patiens cervical lymph nodes, together with an ENT colleague and maybe patient mapped lymphdrainage of different possible application sides, a targeted EBV purge of the affected cervical lymph nodes might be possible?
With less effort, a sonographic study pre and post s.c. application could show signs of hyperperfusion of the LN due to inflammation after cell-lysis in those nodes?
In context of the EBV+ nodes in MS (4-5) and a possible role of the glymphatic system it might be worth a shot.
And thank you again :)
References.
1) Pathways for Cervical (lymphatic) Metastasis in Malignant
Neoplasms of the Head and Neck Region Wang et al. 2012 https://pubmed.ncbi.nlm.nih.gov/21853469/
2) Ofatumumab vs Ocrelizumab s.c. in mice: Torres et al. 2022 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366925/
3) EBV lymph node swelling patterns in children: Abdel-Aziz et al. 2011 https://pubmed.ncbi.nlm.nih.gov/21320728/
4) Lymph nodem in a patient with PPMS. Serafini et al. 2014 https://academic.oup.com/jnen/article/73/7/729/2526047
5) EBV in jugular (deep) CLN and supraclavicular CLN in Patients with MS: Van Zwam et al 2008 https://link.springer.com/article/10.1007/s00109-008-0421-4
6) glymphatic impairement in MS Carotenuto et al. 2022 https://pubmed.ncbi.nlm.nih.gov/34919648/
Good idea. I am aware of a few groups planning to work on deep cervical lymph nodes. Let's hope they find EBV.
Prof G, you are the one to lead this discussion! Below is how I've been describing the options to treat EBV. You did not include option 3, restor immune tolerance to MBP. Does this not seem feasible to you?
Treating Epstein Barr (EBV) as a cause of MS is planned or currently underway in multiple trials. The approaches can be grouped into four categories.
1) Diminishing the viral load of EBV with antiviral or antiretroviral treatments with currently available drugs, which is the subject of this profile. None of these currently approved drugs are optimal for EBV so the question is, can they fill a stop-gap role while more effective therapies are designed specifically for EBV? Also, May 2023 the Immunic trial of Vidofludimus Calcium reported a strong antiviral effect against EBV.
2) Selectively removing EBV-infected B cells with modified T cells (e.g. ATA188 by Atara; Imotope peptide by Imcyse).
3) Rather than directly remove EBV as in the first two approaches, restore regulatory and inflammatory T-cell balance, to induce immune tolerance to MBP. There are currently 10 trials to correct intolerance to myelin basic protein due to molecular mimicry caused by EBV (e.g. ANK-700 peptide, LPX-TI641 activates the Tim3 and Tim4 receptors, to boost expansion of Tregs, and multiple mRNA therapeutic vaccines).
4) Combing one of the first 3 options with remyelination or neurodegenerative repair therapies, some of which are already showing positive results in trials (e.g. MSC stem cells, CNM-Au8 Nanocrystalline Gold, NVG-291 and others)
I’m sincerely hoping that your approach is taken seriously and there will be funding. I admit what immediately came to mind was what Stephen voiced. Stick to it!! Best regards, Prof G with your presentation.
This week's article was very hard to follow for a ley person like me. A single silver bullet has long since been ruled out for MS leaving the collusion of one or more factors being likely.
* Is EBV a catalyst? Some have suggested covid has triggered MS too? Both viral. Why does EBV activate in some people to cause IM? Why did Covid-19 kill a small number of people who fell outside the high-risk groups?
* And what of the role of stress testing? By putting the body under undue load e.g. childbirth, stroke, serious injury appears to make the body vulnerable to attack.
As you say, big data may provide the answers and join the threads together because they seem disparate at the moment.