Saturday, April 23, 2011

Roadmap To Curing Type-1 Diabetes

This posting is a draft.  But I've been working on it for so long that I decided to publish what I have while continuing to refine it.  It's not perfect as-is, but I've decided that it is good enough to publish.

I've been posting a lot of narrow updates recently.  By narrow, I mean "treatment X passed milestone Y" kind of thing: a lot of detail on a very specific treatment.  This posting is the opposite, it is my attempt to put all those narrow postings into context. It is an overview of how we can cure type-1 diabetes using the research that is going on right now.  That cure is still a long way off, but this posting describes the possible paths between here and there.

Please remember that this is a posting about possibilities!  By listing a line of research here, I'm not saying that I think it will work.  All I'm saying is that researchers are actively working on it.  I'm sure that in the end most of the research listed here will fail.  That doesn't matter.  If one succeeds, then it doesn't matter how many fail.  Also, I fully understand that not everyone thinks that all the "cures" listed below are legitimate cures for type-1 diabetes.  Feel free to ignore the ones that you don't consider cures.

First, A little terminology:
Pancreas is the organ that contains specific structures called isletsIslets contain beta cells, which are the exact cells that generate insulin. 

When the immune system mistakenly attacks cells of it's own body, that is called autoimmunity.  If the attacked cells are beta cells, that creates a disease called type-1 diabetesAutoimmunity can target other cells, in which case the disease will have different names and different symptoms.

The immune system attacks beta cells with killer T-cells.  Those specific killer T-cells which attack beta cells are often called "bad" killer T-cells or autoreactive killer T-cells.  Killer T-cells in general are held in check by regulatory T-cells, which are often called T-regs.  Also within the immune system are B-cells (not to be confused with beta cells, which are in the pancreas), and those cells communicate between T cells to encourage them to attack certain cells.

There are many different types of T-cells and B-cells, and they are often identified by CD numbers.  So a T-cells might be described as a CD3 T-cell or a CD8 T-cell.  B-cells might be CD20.  A cell is not limited to one CD number, you could have CD4+CD25+ T regulatory cells (for example).

How to Cure Type-1: Overview

Type-1 diabetes is caused by the body's own immune system mistakenly destroying beta cells in the pancreas.  These beta cells would normally create the insulin the body needs.  Current research is following five basic paths to try to cure it (labeled A-F below) and many of those basic paths have different sub-paths, which I've numbered. 

A. Replace the Beta Cells
Replace the patient's beta cells with ones that can not be attacked by the immune system, so the are not effected by autoimmunity.   Simply replacing beta cells is not likely to be a cure, since the autoimmune attack will destroy the new ones same as the old ones.
  1. Encapsulated islet cells.  Wrap the cells in a membrane which allows nourishment and sugars in, waste products and insulin out, and also prevents immune cells from attacking the beta cells on the inside.  LCT is in phase-II trials and has permission to sell this in Russia but the current results are not a cure, and there are separate phase-I trials in Belgium and Australia.
  2. Elecro-mechanical pancreas (Artificial Pancreas).  Build a pump and sensor replacement pancreas that can measure blood glucose and dose insulin.  The term "Artificial Pancreas" usually refers to using current pump and current CGM sensor technology, so both of these things use external hardware, and the sensors measure BG levels just below the skin, not in blood veins.  There are at least three groups in phase-I or phase-II trials.
  3. Sertoli cells.  There are cells in a human body which are not genetically the same as the rest of the cells, and yet are not attacked by the body's immune system.  An example are sperm cells; which only contain half the genetic material as regular body cells.  They are quite different than regular cells, yet are not attacked as foreign by the immune system.   This is because there are special cells, called Sertoli cells, which block the immune system.  A possible cure for type-1 diabetes it to combine beta cells and Sertoli cells in a transplant that would not need immune suppressive drugs.  Not in clinical trials, although has been in the past. Sernova is doing animal trials in Canada.
  4. Implanted elecro-mechanical.  Similar to the artificial pancreas described above, except that implantation means that the blood glucose sensor can be put directly into a blood vein, and resupplying with insulin and new batteries is more of a problem.  Also, this is internal, so not visible outside of a person.  At least one was in phase-I trials in the past; not sure if any are now.  (Dr. Rennard's work in France is with an implanted pump, not an implanted artificial pancreas.  So is headed in this direction, but not quite here, yet.)
  5. Non-pancreatic beta cells.  In the last decade we have learned a little bit on how to take adult stem cells and program them to become other types of cells.  So a possible cure for type-1 diabetes would be to take adult stem cells or even just normal cells from the liver, and program them to produce insulin in response to glucose.  The hope is that since they started out as liver cells, the autoimmune attack would not target them, but they would still generate insulin in response to blood glucose.  Not in clinical trials.
  6. No Moving Parts Artificial Pancreas.  This is similar to "self dosing insulin" (described below), except that there is a chemical barrier that is sugar sensitive, and the insulin is stored behind the barrier.  If the sugar level in the blood is too high, the barrier becomes more permeable and more insulin leaves the reservoir.  Conversely, if the sugar level goes low, the barrier becomes less permeable and less insulin gets out.  Not in human trials; may not even be in animal trials.
I don't consider a classic pancreas transplant or beta cell transplant a cure, because they will require a lifetime of immune suppressive drugs and related complications and side effects. But there is a lot of research going on to improve these procedures.
      B. Stop the Autoimmune Attack
      Stopping the body's immune attack on it's own pancreas is another way to cure diabetes.   Some refer to this as curing the underlying cause of type-1 diabetes, as opposed to replacing the pancreas which they view as curing the symptoms.

      I divide this research into different groups based on how they attempt to stop the autoimmune attack.  Since the immune system is very complex, there are many ways to try to get it to stop, and so many different ways to categorize this research.  The division below is my personal taste.  Different researchers do it differently.

      Any treatment that stops the immune attack on beta cells needs to be focused, so that it does not stop the immune attack on foreign cells.  A "cure" that hobbled the immune system's beneficial functions would be worse than than type-1 (in my opinion), and I would not consider it a cure at all.
      1. Antigen specific targeting
        • GAD65.  GAD65 is one of the proteins on a beta cell which is (mistakenly) attacked by the immune system, and this treatment is an attempt to teach the immune system not to attack that exact protien.  In phase-III trials.
        • Insulin B chain.  Finished phase-I trial.
        • Insulin.
      2. Targeting specific "killer" T-Cells. Modern technology can create monoclonal antibodies which specifically target specific T-cells. 
        • Anti-CD3s.  CD3 are a type of immune cells which are involved in the attack on beta cells.  These treatments target that cell type.  There is currently one (NI-0401) in phase-II trials.  (Two more just failed phase-III trials.)
      3. Targeting communications cells.  Monoclonal antibodies have also been created to target CD20.  Finished phase-II trials. 
      4. Heat Shock Protein 60 (HSP60) is a small protein that might help teach the immune system not to attack it's own body.  Diapep277 is based on this, and in phase-III trials.
      5. Polyclonals.  
        • ATG.   **need more info here**  In phase-II trials.
      6. Raising the level of TNF.  BCG.  TNF is a naturally occurring substance that kills of certain types of cells (especially tumor cells).  If TNF kills off "bad" killer T-cells specifically, then raising TNF levels might put type-1 diabetes into remission or even cure it.  Since BCG is known to raise TNF levels, it is a possible cure for type-1 diabetes.  No results from a phase-I trial.
      7. Reinforcing T regulator cells.
        • Dendric cells. **need more info here** In phase-I trials.
        • T-regs.  **need more info here**  In phase-I trials.
      Note that this path may require that we replace the lost beta cells (see section C), or those cells may regrow without outside help, once the autoimmune attack is stopped.

      C. Create new beta cells to replace those that were lost.
      If the autoimmune attack is stopped by a cure from group B, then it may still be required to regrow, improve, or replace beta cells in order to have a cure.  
      1. Drugs that trigger regrowth.  There are several drugs which might trigger regrowth of beta cells.  These include Human Growth Hormone and Exsulin, which have done some clinical trials, and CureDM, which has not yet.  Exsulin is in phase-II trials.
      2. Stem Cells could be used to grow new beta cells.  Many different techniques, some you can get in a clinic now, some in phase-I, and others still doing animal experiments.
      3. Temporary beta cell replacement.  Any of the cures in group A could also be used to provide new insulin, especially if only needed temporarily while the body's beta cells naturally regrew.
      4. Type-2 drugs. Many of the drugs given to type-2 diabetics work by getting more insulin out of existing beta cells, or having that insulin used more efficiently by cells, so any of them might be helpful here as well.  Several in phase-II trials.

        D. Stop inflammation to stop type-1.
        Most researchers believe that as the immune system attacks the beta cells, it causes inflammation:
                Autoimmunity -> Kills Beta Cells -> Causes Inflammation
        But some researchers believe that the inflammation itself kills the beta cells.
                Autoimmunity -> Causes Inflammation -> Kills Beta Cells
        This difference is important because the second group of researchers believe that if you could stop the inflammation, you could stop type-1 diabetes.  There are a large number of anti-inflammation drugs out there, and new ones are being worked on all the time, so I'm only listing those that are being tested on type-1 diabetes specifically: Anakinra is in phase-II, Lisofylline and Xoma 052 are in phase-I. **need more info here**
          E. Self Dosing Insulin.
          Create a substance that contains insulin, but only makes that insulin available when the blood glucose level is too high.  SmartInsulin, SIA-II, and BIOD Smart Basal are examples of research into this type of cure. Smart insulin is probably in clinical trials now.  (I'm trying to confirm this.)  The other two are not.  **need more info here**

          F. Gut Permeability
          Most researchers believe that gut permeability has nothing to do with diabetes.  But some researchers believe that heightened gut permeability causes the autoimmune response that causes type-1 diabetes.  When more and larger molicules move out of the intestine and into the bloodstream, that over activates the immune system which attacks the cell of the body.   These researchers believe that if you could lower gut permeability, you could prevent or stop type-1 diabetes.  Right now, there are no drugs based on this theory in clinical trials, although in the past Alba Therapeutics talked about testing their AT-1001 drug on type-1 diabetes.  (It is currently only being tested for Celiac disease.)

          Combining Therapies

          Basically A, D, E, and F cures are "one step" if they work, we're done.  But B and C are a little more complex.  B might require C to be a cure, or maybe not, or maybe B will work by itself, but take a very long time, so a practicle cure would still require both B and C.  In any case, it seems unlikely that C alone could cure type-1.  Certainly, we have tried Exsulin, Human Growth Hormone, and many types of beta cell transplants, and none of those have led to a cure.

          Please do remember that this posting is a work in progress, and I do hope to improve it over time.  Please email me with specific parts that are hard to understand, or need more explanation.  This is a case where I think publishing this information now, is better than waiting for perfect, refined information to be ready in the unknown future.
                Joshua Levy
                All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
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                Kathy said...

                I like this as a framework.

                I see this all happening in phases. Islet cell transplants have proven to be effective. These trials should continue while the other issues are being addressed. Pig cells or stem cells would accelerate this research and help so many patients who can't wait for perfection. Encapsulation would be nice, but seems a long way from fruition as far as longevity of the islets.

                My best guess is using a patients own stem cells as the source (in vitro) with an islet cell transplant as the delivery system.

                It is all so exciting to think about. What we really need is a way to accelerate the funding.

                Anonymous said...

                What about Nanotechnology?
                Have you considered it? it seems that it might be a nice solution...
                Maybe I skipped it and it's already mentioned in your nice framework or maybe it's just used to provide proteins or so...

                Joseph said...

                Great overview! I've thought about doing something like this so I could track progress and various research avenues, but it wouldn't have been anywhere near as detailed. I just found your blog today and I will probably be coming back often, you do a good job of covering any news in research.

                Unknown said...

                Congratulations for your research and good work!
                I'm glad to see that someone else is also researching possible ways to cure type 1 diabetes. I've been doing that for 15 years although not so scientifically as you do here.

                I recently autopublished a book abou the topic in Spanish and now I'm translating it and publishing chapter after chapter on my blog.

                Since I'm donating 10% of the sales to a diabetes cure research project, I would like to know which research or project do you find the closest to find a cure?

                Your answer would be much appreciated.

                Keep up the good work!