They could be on to something

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

They could be on to something

Postby dignan » Sat Aug 27, 2005 11:36 am

I don't know if I've connected the dots properly, but here it goes:

In 2001, UC Irvine researchers found that ShK, a sea anemone venom halted and reversed EAE.
http://www.ucihealth.com/News/Releases/ ... one_ms.htm

ShK appears to work by blocking a specific voltage-gated potassium channel, Kv1.3. ShK is the most potent known inhibitor of Kv1.3.

The problem is that ShK doesn't last long enough in blood to effectively treat MS. So the researches started playing around with the molecule to see if they could make something that would work as an MS treatment.

Earlier in 2005, this same group of researchers appear to have found something new. They have created a novel peptide -- ShK(L5) -- that has the effects of ShK, but is more suitable as a potential MS treatment. It appears to work well in the EAE model.
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Citation

In July, another group of researchers has done a post-mortem study of the brains of people with MS and confirmed that the Kv1.3 potassium channel seems to be more highly expressed in MS lesions AND in the normal appearing white AND grey matter in the brains of people with MS. I hope by this they mean that interfering with Kv1.3 could help stop lesions AND axonal degeneration.
http://www.pnas.org/cgi/content/abstract/102/31/11094

Finally, one other common thread all these studies have is Dr. Peter Calabresi from Johns Hopkins. He also happens to be the leader of the group at Johns Hopkins that just received part of the $15 million grant from the US MS Society. This group is "searching for better ways to detect and quantify tissue injury in MS and testing agents that may protect the nervous system from further damage."
http://www.nationalmssociety.org/promise2010.asp

It seems that they have the money to really run with this now. Hopefully we'll soon be hearing about human trials of ShK(L5). (hopefully they rename it something a bit catchier...let's see...the name "Tysabri" is already taken...hmmm...)

That's it.
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 2:00 pm

Advertisement

Postby dignan » Thu Sep 08, 2005 7:15 am

Just saw this story that another one of the scientists involved in these studies has be given an award, and more importantly, a truckload of money. It seems that in general, the research they are doing into ion channels must be considered important if the National Institute of Neurological Disorders and Stroke and the MS Society are both giving large awards to scientists pursuing this avenue of research. I hope it's justified.



NINDS Javits Award Goes to Six Inventive Neuroscientists

The Award guarantees funding for 4 years, after which 3 additional years may be awarded pending receipt and approval of additional information. Investigators are nominated by either NINDS staff or members of the National Advisory Neurological Disorders and Stroke Council, from a pool of competing applicants during a grants cycle. The Council must approve each recommendation, with final selection being made by the NINDS Director.

Recipients of the Senator Jacob Javits Award in the Neurosciences are:

Michael D. Cahalan, Ph.D., Professor of Physiology and Biophysics, University of California at Irvine.
An immunologist, Dr. Cahalan is deeply interested in how T lymphocytes ( white blood cells that help the body fight off infection ) function at the molecular and cellular levels. He is also interested in diseases such as multiple sclerosis, which are thought to have an immune component. T lymphocytes possess numerous ion channels, which are intimately involved in the immune response and offer promising targets for development of immune system therapeutic agents. His Javits award will allow him to study the role calcium release-activated calcium channels play in T cell responses, as well as to identify the molecular basis for channel gating and the corresponding cellular response in immune system activity.

http://i-newswire.com/pr45645.html
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 2:00 pm

Postby dignan » Sun Jan 14, 2007 2:02 pm

I'm updating this old thread because the new info is related to the same potassium channel (Kv1.3) that ShK(L5) targets and which is implicated in MS. This company sounds interesting because their drug-candidate will be oral. It's still a long way off though, they haven't even selected a pre-clinical candidate.



Kv1.3 Blockers for Multiple Sclerosis

Multiple sclerosis (MS) is a severe and debilitating disease caused by the autoimmune destruction of myelin tissue surrounding neurons.

The disease affects nearly one million people in the developed world alone. Current treatments have little impact on long-term disease progression.

All existing treatments for this chronic disease are in the form of injections. A major unmet need in MS therapy is the development of an oral medication.

Bionomics is developing a new generation of Multiple Sclerosis treatment, based upon blockers of the Kv1.3 potassium channel.

Kv1.3 is a key regulator of the effector-memory T-Cells of the immune system that are the key mediators of disease in MS. Kv1.3 is expressed in a limited range of tissues, lowering the likelihood of side-effects. Bionomics has identified what it believes to be the most promising inhibitors of Kv1.3 of any program in the world.

Bionomics' compounds have excellent potency (better than 25nM), very good specificity for Kv1.3 over other ion channels and very drug-like characteristics. Efficacy has been demonstrated in animal models of MS.

Importantly, Bionomics' Kv1.3 inhibitors exhibit excellent oral bioavailability.

The Company expects to select a clinical candidate in 2007.

http://www.bionomics.com.au/page.php?section=105
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 2:00 pm

Postby Lyon » Mon Jan 15, 2007 1:09 pm

I'm glad you updated it because I hadn't previously noticed this thread.

I don't think I've ever seen a situation before where a company says that they want to hold a clinical trial and are in the process of finding something to test.

Bob
Lyon
Family Elder
 
Posts: 6063
Joined: Wed May 03, 2006 2:00 pm

Progesterone and Kv1.3 Potassium Channel Inhibition

Postby Shayk » Mon Jan 15, 2007 4:53 pm

Lyon
they want to hold a clinical trial and are in the process of finding something to test.

I've posted it before, but now I get to post it again. 8) I say they may not need to look too far. There's an oral (or cream) hormone on the market, progesterone, that blocks those Kv1.3 potassium channels.

A Nongenomic Mechanism for Progesterone Mediated Immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes

K+ channel blockade by progesterone is specific; other steroid hormones had little or no effect,…..

Progesterone effectively blocked a broad spectrum of K+ channels, reducing both Kv1.3….

We propose that direct inhibition of K+ channels in T cells by progesterone contributes to progesterone-induced immunosuppression.


Something else that might be relevant is to be certain we have a sufficient amount of Vitamin B 1 (thiamine). Deficiencies of thiamine present some interesting problems, and thiamine apparently also inhibits potassium channels, although I don't know if it's specific to Kv1.3.

The problems.....
Thiamine Deficiency and Metabolic Acidosis
Thiamine deficiency (TD) in both humans and experimental animals results in severe compromise of mitochondrial function and leads to selective neuronal cell death in diencephalic and cerebellar structures.


Reversal of Thiamine Deficiency Induced Neurodegeneration
Neurodegenerative diseases are characterized by abnormalities in oxidative processes, region-selective neuron loss, and diminished thiamine-dependent enzymes. Thiamine deficiency (TD) diminishes thiamine dependent enzymes, alters mitochondrial function, impairs oxidative metabolism, and causes selective neuronal death…..

The good news—thiamine apparently has some potassium channel blocking properties.

Thiamine and Its Derivatives Inhibit Delayed Rectifier Potassium Channels in Rat Cultured Cortical Neurons
We examined the effects of thiamine and its derivatives on voltage-gated ion channels of neuronal cells ….
These results suggest that phosphorylated thiamine can function as an endogenous K+ channel blocker in neuronal cells.


Legs--(or anyone else) if you've already posted this I apologize. I accidentally stumbled across the info, but I don't know what “phosphorylated” thiamine is. Can you clarify? I think thiamine is Vitamin B 1 and I don't want any deficiencies in that or progesterone :wink:.

Sharon
User avatar
Shayk
Family Elder
 
Posts: 779
Joined: Fri Feb 06, 2004 3:00 pm

Postby Lyon » Mon Jan 15, 2007 6:01 pm

I don't know how you came up with that stuff so fast Sharon but that was good work!
Bob
Lyon
Family Elder
 
Posts: 6063
Joined: Wed May 03, 2006 2:00 pm

thiamin and potassium and magnesium, oh my!

Postby jimmylegs » Mon Jan 15, 2007 7:35 pm

hiya, i might have posted it not sure. but yes you are right thiamin is B1. phosphorylated would be, chemically tied up with a phosphate (phosphorus with some oxygen). http://en.wikipedia.org/wiki/Phosphorylation

Forms of the vitamin

Thiamin is found in most animal tissues predominantly in phosphorylated forms (e.g., thiamin mono-, di- and tri-phosphates). ... thiamin is found in the diet in one of three forms: free thiamin, phosphorylated thiamin, and protein-phosphate complexes.


http://orsted.nap.edu/openbook.php?record_id=949&page=44

i started in on the potassium channel reading, and next thing i knew in comes my brother complaining of scary heart palpitations, he was on the phone to telehealth the night before, and i was thinking... ooo, i've read about a nutrient for this so recently... what was it... and next he said that his eye was all twitchy too and i said a HA! magnesium (coz i think in the final analysis, this is what manages the jimmylegs the best coz when my eyelid gets twitchy i take magnesium and the jimmy calms down too) and looked it up and yes. links between cardiac arrhythmia (right up to sudden death from heart failure) and magnesium deficiency, all over the research.

so hopefully he's all calcium and magnesium'ed up now and so then when he left, i went back to my potassium channel reading stemming from this ms forum thread, and it went straight into talking about cardiac function being dependent on potassium channels, and potassium channels being dependent on the presence of magnesium ions.

so then we get back into the usual tangled web - guess what we need to absorb magnesium, that's right sunshine girl says d3, (and calcium) and guess how we DON'T get magnesium, that's right by putting our water through the brita, and guess how you shovel magnesium and calcium out of your body like mad via urinary excretion, that's right have a coffee... come on, everybody's doing it!

so anyway, point being, if we want our potassium channels to do what they're supposed to do, we have to put magnesium in there, make sure it absorbs, and then not dump it out again with coffee (and/or alcohol). bummer ;)
jimmylegs
Volunteer Moderator
 
Posts: 9151
Joined: Sat Mar 11, 2006 3:00 pm

Postby dignan » Mon Jan 15, 2007 8:25 pm

Another newish abstract about Kv1.3 from the group at UC Irvine.



Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17414-9.
Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, S Andrews B, Sankaranarayanan A, Homerick D, Roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus HG, Nepom GT, Gutman GA, Calabresi PA, Chandy KG.
Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naive or central-memory (T(CM)) cells.

In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats.

Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Pubmed reference
Last edited by dignan on Tue May 06, 2008 3:15 pm, edited 1 time in total.
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 2:00 pm

Postby dignan » Mon Jan 15, 2007 8:29 pm

And here's one for Lyndacarol about Kv1.3 and insulin.



A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance.

J Clin Endocrinol Metab. 2006 Feb;91(2):654-8.
Tschritter O, Machicao F, Stefan N, Schafer S, Weigert C, Staiger H, Spieth C, Haring HU, Fritsche A.
Medizinische Universitatsklinik, Otfried-Muller-Strasse 10, D-72076 Tubingen, Germany.

CONTEXT: The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed in a variety of tissues including liver and skeletal muscle. In animal models, knockout of Kv1.3 has been found to improve insulin sensitivity and glucose tolerance.

OBJECTIVE: We examined whether mutations in the Kv1.3 gene exist in humans and whether they are associated with alterations of glucose homeostasis.

DESIGN AND SETTING: We conducted a genotype-phenotype association study at a university hospital.

PARTICIPANTS AND METHODS: In 50 nondiabetic subjects, we screened approximately 4.5 kb of chromosome 1 comprising the single exon, the promoter/5'-untranslated region, and the 3'-untranslated region of the human Kv1.3 gene for mutations by direct sequencing. Subsequently, all identified single-nucleotide polymorphisms were analyzed in 552 nondiabetic subjects who underwent an oral glucose tolerance test (OGTT). Of these, 304 had undergone an additional hyperinsulinemic euglycemic clamp.

MAIN OUTCOME MEASURES: We assessed postprandial blood glucose during OGTT and insulin sensitivity measured by hyperinsulinemic euglycemic clamp.

RESULTS: We identified five single-nucleotide polymorphisms in the promoter region (T-548C, G-697T, A-845G, T-1645C, and G-2069A) with allelic frequencies of the minor allele of 26, 23, 9, 41, and 16%, respectively. The -1645C allele was associated with higher plasma glucose concentrations in the 2-h OGTT (P = 0.03) even after adjustment for sex, age, and body mass index (P = 0.002). In addition, it was associated with lower insulin sensitivity (P = 0.01, adjusted for sex, age, and body mass index). Functional in vitro analysis using EMSA showed differential transcription factor binding to the T-1645C polymorphism.

CONCLUSIONS: We show that a variant in the promoter of the Kv1.3 gene is associated with impaired glucose tolerance and lower insulin sensitivity. Therefore, the Kv1.3 channel represents a candidate gene for type 2 diabetes.

Pubmed reference
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 2:00 pm

Postby Arron » Tue Jan 16, 2007 2:40 am

just wanted to cheer you guys on. Connecting these dots is exceedingly difficult-- and we owe a debt of gratitude to those that put in the time and energy to try and figure out what seems to be a highly complex condition. Keep going... you may be just around the corner, or you may already be there... :)
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
User avatar
Arron
Volunteer Moderator
 
Posts: 892
Joined: Sun Feb 01, 2004 3:00 pm
Location: California, USA

ty

Postby jimmylegs » Tue Jan 16, 2007 4:45 am

thanks aaron :)
jimmylegs
Volunteer Moderator
 
Posts: 9151
Joined: Sat Mar 11, 2006 3:00 pm

more for LC

Postby jimmylegs » Wed Jan 17, 2007 6:13 am

so, it appears thiamine is not only good as a potassium channel blocker ... LC have you seen this angle before?

Lipophilic thiamine treatment in long-standing insulin-dependent diabetes mellitus
Journal Acta Diabetologica
Issue Volume 36, Numbers 1-2 / July, 1999

Authors
G. Valerio, A. Franzese, V. Poggi, C. Patrini, U. Laforenza, A. Tenore
Abstract

Thiamine plays an important role in the regulation of glucose metabolism and pancreatic #-cell functioning. A role for this vitamin in cellular glucose transport has been indicated in the literature. The aim of this study was to determine whether a lipophilic form of thiamine (benzoyloxymethyl-thiamine, BOM) was able to improve metabolic control in patients with long-standing insulin-dependent diabetes mellitus (type 1). A total of 10 children with type 1 diabetes of long duration (age 11.4 - 1.2 years, duration of the disease 4.5 - 0.7 years, means - SEM) were studied before and after treatment with BOM in a randomized double-blind and placebo-controlled study. Five patients were assigned to the BOM-treated group and five to the placebo-group. In all patients basal and glucagon-stimulated C-peptide secretion was undetectable. Thiamine status was assayed by measuring the plasma content of thiamine and its monophosphate form at entry and after 3 months of treatment. The blood HbA1C levels and the daily dose of insulin per kg body weight were assessed in both groups before treatment, after 1 month and 3 months of treatment, then 3 months following its suspension. The plasma content of thiamine + thiamine monophosphate in type 1 diabetic patients (35.3 - 3.6 pmol/mL) was significantly lower when compared with that measured in six age-matched normal subjects (53.2 - 2.3 pmol/mL, P < 0.05).

The association of dietary fibres with glucose tolerance is partly explained by concomitant intake of thiamine: The Hoorn Study
Authors
S. J. L. Bakker, E. K. Hoogeveen, G. Nijpels, P. J. Kostense, J. M. Dekker, R. O. B. Gans, R. J. Heine
Abstract

Summary Epidemiologic studies have shown an association between the intake of dietary fibres and 2-h glucose values. Food rich in dietary fibres is often also rich in thiamine. Animal studies have shown that thiamine deficiency can induce glucose intolerance. Our aim was to investigate the association between fibre consumption and thiamine intake on the one hand and glucose tolerance on the other hand. We used data from the Hoorn Study, a study of glucose tolerance among 1008 men and 1188 women, aged 50-75 years, without diabetes. In linear regression analyses, fibre intake was inversely associated with fasting glucose. There was also an inverse association between fibre intake and 2-h glucose but it disappeared for the greater part after adjustment for fasting glucose. Fibre intake appeared to be strongly correlated with thiamine intake, and this correlation explained the remaining part of the association between fibre intake and 2-h glucose. Thiamine intake appeared to have a strong and relevant association with 2-h glucose, which was independent of fibre intake and fasting glucose. This association was borderline after adjustment for potential confounders. In women, but not in men, the effect of thiamine intake on 2-h glucose seemed to be modified by fibre intake, independent of potential confounders. In conclusion, part of the association between fibre intake and glucose tolerance is possibly attributable to concomitant thiamine intake. [Diabetologia (1998) 41: 1168-1175]
jimmylegs
Volunteer Moderator
 
Posts: 9151
Joined: Sat Mar 11, 2006 3:00 pm

Thiamine/potassium channel blocker news

Postby lyndacarol » Fri Jan 19, 2007 6:39 pm

Legs, my computer "died" last weekend. I only got it back this afternoon, so I'm spending the evening going through LOTS of postings.

This is news to me--I have not heard it before. I am interested in this thiamine/ potassium channel blocker idea.

But, coincidentally, the health segment on local news this afternoon was about a 7 year old girl, who was diagnosed with Type 1 diabetes at 6 months, and who now had been discovered to have a genetic reason for it--problem with potassium channels. She now takes Glycobide (or SOMETHING like that--I didn't catch the drug. Sorry I don't have all the details.) and no longer uses insulin, tho she does check glucose twice a day (rather than ten times as previously)
User avatar
lyndacarol
Family Elder
 
Posts: 2385
Joined: Thu Dec 22, 2005 3:00 pm

glyco-something

Postby jimmylegs » Fri Jan 19, 2007 8:20 pm

hey that's interesting lc good one.
jimmylegs
Volunteer Moderator
 
Posts: 9151
Joined: Sat Mar 11, 2006 3:00 pm

Postby dignan » Tue Apr 08, 2008 6:57 am

More on the UC Irvine group's efforts...


Sea Anemone Venom Can Treat Autoimmune Diseases

Researchers at UC Irvine’s College of Medicine have refined a treatment that uses a toxin from sea anemones to treat autoimmune diseases. Autoimmunity triggers an immune response in which white blood cells attack the body’s own organs, resulting in diseases such as multiple sclerosis (MS), rheumatoid arthritis and Type-I diabetes.

“Autoimmune diseases affect millions of Americans, and any new therapies that can aid them will have great significance,” said George Chandy, a UCI School of Medicine researcher and head of the group developing the formula, in a 2006 press release. “What’s promising about this study is that we identified a protein target on the T-cells that promotes autoimmune activity and the compounds that can selectively block the target and shut down the destructive cells.”

Work on the treatment began when Chandy, Christine Beeton and several colleagues came across a report describing the improvement of symptoms in a patient with multiple sclerosis following a scorpion sting. The venom contained a peptide that blocks a certain potassium channel which is necessary for the self-attacking T-cells to survive. By blocking the channel, the treatment causes immobility in the T-cells. With no way of survival, the destructive T-cells die off, allowing other white blood cells to fight disease and infection.

After this initial discovery, the team began screening several other toxins and their modifications to find one with favorable characteristics in order to produce a marketable formula.

The treatment has been modified since its inception, as new compounds are tested and added to make the treatment more stable and have a longer half-life. The current formula is based on a toxin derived from sea anemones combined with many other modifications. The peptide has had multiple modifications thus far.

“It’s been a constant process of [refining] the formula,” said Victor Chi, a second-year graduate student working on the project.

Researchers on the project have also changed as Beeton left UCI for a position at the Baylor College of Medicine. The research is now led by Chandy. Chandy’s research team consists of post-doctoral staff member Srikant Rangaraju, M.D., as well as graduate students Adriana Garcia, who specializes in physiology, and Chi.

Chi went on to describe his enthusiasm for the project.

“It’s good to see something you have been working on help other people,” Chi said. “Most people don’t get to see the real-world value they make in their lifetime. … In what we are doing, there is a probability that we will see real-world results.”

Drug trials done on rats and human blood cells have proven to be successful. If the treatment is successful on human beings, it could result in a new class of drug treatments for a multitude of autoimmune diseases.

“My aunt has MS … and she recently had a baby,” Garcia said. “I really hope that this [formula] gets out into the market and [makes] an impact.”

http://www.newuniversity.org/main/article/143
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 2:00 pm

Next

Return to General Discussion

Who is online

Users browsing this forum: No registered users


Contact us | Terms of Service