POSSIBLE SPORADIC ALS/MND TREATMENT STRATAGIES.

ALS/MND and many other diseases are first phase chronic cellular regeneration diseases. Knowing this helps to determine possible treatment strategies. If the first phase of regeneration is chronically activated, there are two main possibilities to look at; stop the first phase from starting; or force the commencement of the second phase of regeneration to start. Any successful treatment should do one of those two things.

An advantage of stopping the commencement of cellular regeneration is that it may be possible to stop the chronicity of the disease and create a real cure. If it is not a real cure, the treatment would have to be administered intermittently to protect unaffected cells. It is important that any treatment stops only the regeneration process in the type of cell involved, or at the worst, the lineage of the cell involved.

Forcing the commencement of the second phase of regeneration will probably be easier to achieve, but this is likely to only be a treatment as the cause will always be trying to overcome the treatment. This will also probably be easier to treat a single cell type, (once the disease is fully understood).

It could be possible to knock-out something that is a necessity for the first phase of regeneration, (e.g. inhibit p8 with p8 RNAi) and thus allow the progression to second phase regeneration. The danger of this is that if the treatment is required continuously; because the cause will still be active; the treatment would only work for a short time period. The treatment would then help up regulate the cause; the cause and the treatment both halt first phase regeneration; creating a more aggressive disease. The treatment would have to be administered in short bursts with sufficient dwell periods between treatments. These dwell periods have to last long enough for unaffected cells to go through regeneration if required.

For a quick explanation of my theory on chronically activated cellular regeneration and "THE COMMON EVENT" that results in all phenotypes of ALS/MND see my post on the forum December 23, 2011. No biomarkers to definitely diagnose ALS...Really!!

---

David Hicks.

Dave, the "mister" above is a bit formal, David is better. You have asked me to do what I think will take me all year to do properly. My aim is to give ALS TDI so many examples of how my theory works they won't be able to ignore it. And if they are not interested I will find someone that is.

My theory is so deceptively simple, that it is hard for anyone to see its potential without very extensive explanation. The few basics apply to dozens of diseases, so when the medical profession finally understands this, it will be one of the biggest medical discoveries for many years. I am presently preparing some brief examples on the types of results you will find if you seriously investigate the flow on discoveries that follow the understanding of "THE COMMON EVENT". I will try to do as you wish after I finish this.
Dave, I will email you a copy of what I have written on my theory so far.

---

David Hicks.

Dave,
I have to use words like, may, could, would, should, probably and proposed as I found out that in this forum you get jumped on very quickly if you use positive words like, is, can and will, without reference to proven research. The worst of all of them is a statement that "X" causes ALS.
Even though I think that what I write is correct, or has a good chance of being correct, there is no way that everything I write is correct.
I believe that my ability lies in the fact that I tend to see things that other people don't see. I have spent an average of 40 hours a week over the last 9 years studying medicine and all sorts of diseases. It is this wide field of knowledge that allows me to see possibilities that the specialists can't see. My vague generalities are meant to give ALS TDI something new that they can investigate, and not just something they can read themselves in a research paper. This is the type of thinking that great advancements in medicine come from. Just understanding 'THE COMMON EVENT' is going to lead to an enormous rush of medical discoveries over the coming years. (Sorry, more generalities).

---

David Hicks.

Sorry this is not the promised post on mTOR. It is taking me longer than I thought as mTOR is very complex.
This is a quick proposal on the possibility of halting IGF-2 as a treatment for sporadic ALS.

More research should be aimed at finding the cause of the disease process in ALS/MND before trying to find the cure. Once you find the causes and variations of ALS, it opens up many possibilities of potential treatments that will actually have a chance of success.

A lot of research has been done trying to see if an IGF-1 treatment will help in ALS, but no one bothers to investigate the interconnecting role of insulin, IGF-1 and IGF-2. It has just been assumed that if the normal role of IGF-1 is not working, just adding IGF-1 should fix it.

What you need to know before trialling IGF-1 is why is IGF-1 not working? With reading existing research papers you can find that during the first phase of cellular regeneration, the insulin pathway is down regulated, IGF-1 is available but mainly ineffective, and IGF-2 is very highly up regulated. IGF-2 is able to form a ligand with insulin, IGF-1 and IGF-2 receptors with high affinity. IGF-1 is thought of as a non-classical neurotrophic factor and is known to be expressed mainly in connective tissue such as muscles etc.

If you understood the cause of sporadic ALS, you would probably find that a chronic injury or insult in connective tissue muscles connected to motor neurons will actually inhibit motor neuron regeneration exclusively. This would cause sALS but not fALS.

Now back to known reality. The very highly up regulated IGF-2 will ligand with most of the IGF-1 receptors, leaving only a small number of receptors for IGF-1. IGF-1 is required in the second phase of cellular regeneration. This would occur only in a few hours time under normal regeneration requirements, but in chronic conditions this may be years, and this will restrict motor neuron regeneration for years also. Adding low levels of IGF-1 is unlikely to alter the situation as there is still free IGF-1 available but no receptors to ligand with. Adding very high levels of IGF-1 as a treatment may out compete some of the IGF-2, but the IGF-2 will always be fighting the treatment.

The solution is: HALT THE EXPRESSION OF IGF-2 (NOT ADD IGF-1).

This will have a very good chance of providing a benefit for sporadic ALS, but it will be of no benefit to familial ALS or the mSOD1 mouse, so it is of no use testing the theory on the SOD1 mouse. There is a down side to halting IGF-2 as a treatment, as this will cause the cessation of the first stage of cellular regeneration in all connective tissue, bones and teeth; so the treatment will need to be intermittent.

---

David Hicks.

Thanks David for posting all of that.

Very well laid out and certainly a good read for getting handle on SAL's.

When you said, 'This means that most of the worst failures trialled on the SOD1 mouse would make the best treatments for human sporadic ALS patients.'

That is why I keep on about genetic target selection when undergoing trials in PALS is so important.

Once again many thanks for all the work you have put in.

---

Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

The lack of markers or the means to differentiate between the different forms of ALS is holding back ALS research. I think that at this stage, more effort should be placed on the causes of ALS and the pathways involved. Once these are understood, possible markers will start to present themselves everywhere. Real cures or very effective treatments will then follow.

Existing research is just a guessing game. i.e. This has something to do with ALS, so lets try stopping it to see if it will make a treatment for ALS. Most research doesn't even try to separate familial ALS from sporadic ALS.

---

David Hicks.

Hi David

Thank you for your comprehensive reply to my post, it is much appreciated. I am very intrigued by your hypothesis and wish to digest this a bit more as I'm convinced my problems started in the muscle.

Merc

David,
Irene is obviously a woman, taking osc and seeing some results from it. She was on HRT tablets until her diagnoses and she stopped them. I wouldn't say she was overweight at the time of disease onset but she would have a tummy if that is what adipose tissue means. Would she benefit from estrogen and is it available prescription only or an over the counter drug? She is post the menopause.

As an aside you mention axon growth is the rate of 1 metre per annum. Irene's physio says it is roughly 1mm per day i.e.1000days to grow 1000mm. Is that not right? Also I believe there are only legs where you would have that sort of need ,elsewhere in the body the axon are considerably shorter.

John

This follows on from my last post where I didn't put a link to my article on peripheral arterial disease (PAD). Although written for PAD, it is equally relevant for sALS.

Proposed Treatment for Peripheral Artery Disease (PAD).

Aim of the treatment: For middle age to elderly women. There may be some unwanted side effects for men.

To raise the female oestradiol level to a constant level; not over 40 picomils per litre?
Hopefully this will most easily be obtained by the administration of a monophasic oral contraceptive pill administered daily, or a specifically designed treatment. The general safety of the dosage of the contraceptive pill has been proven over many years, with the exception of a slight possibility of some cancers (e.g. breast cancer), if used over a very long time frame.

Mode of operation:

Oestrogen is known to instigate foetal cell growth.

This cell growth is different to the adult cellular repair mechanism. In the adult cellular repair mechanism there is the requirement to analyse the form of the insult, orchestrate the immune system, and mobilize cells and defences against any insult. Multiple changes are made to combat any threat, such as; the vasodilator eNOS is down regulated and vasoconstrictor ET-1 is up regulated causing capillaries and vasculature to constrict, to minimise possible blood loss. PAI-1 is up regulated resulting in down regulated fibrinolysis and vascular occlusion; up regulated NFкB, PARP and AP-1 induce gene expression that initiates innate and adaptive immune responses. There are many, many more changes made, but these are the most pertinent to peripheral artery disease (PAD/PVD).

Oestrogen induced foetal cell growth (using mitosis), does not require any of the above changes as there is no injury or insult to consider. One of the main differences in the two processes is that adult mitosis initiates IGF-2 expression as well as all of the above changes. On the other hand oestrogen initiates IGF-1 and growth factor (GF) and mostly none of the above changes. It appears that oestrogen has a similar effect as p57KIP2, (this still has to be proven), p57KIP2 is a maternally expressed imprinted gene that is antagonistic to IGF-2. In this way, oestrogen probably shuts down and forces the exit of the first growth phase (G1/S) of any chronic adult mitosis and allows the G2 phase allowing the finalization of cellular repair.

Why is this important? It is not commonly accepted knowledge yet that many diseases including cancer, diabetes and neurological diseases that are currently thought of as inflammatory-like conditions, or failures of the autoimmune system, are the result of a chronic failure of the first phase of cellular regeneration.

In the case of PAD, there will be a chronic injury or insult in the beta lineage, (connective tissue – muscle, tendon, bone, etc.), that causes the cellular regeneration process to become stuck or stalled in the first phase (G1) of cellular regeneration. In this phase, apoptosis and the immune system is down regulated. As long as oestrogen down regulates IGF-2, (in women), and up regulates IGF-1, it will break the chronic condition of the causal disease wherever it is, and allow normal cell growth to occur. As skin cells are replaced very quickly, there should be evidence of efficacy of oestrogen supplementation showing up in PAD in a short time frame.

One of the important possibilities of this proposal is that if it works, it will reinstate a normal working immune system and allow antibiotics to work efficaciously. During the adult cellular repair mechanism, the vesicle-associated LC3II form of autophagy causes an antigen presenting cell, (monocyte or macrophage), to express MHC class II which ligands with CD4+ on a naїve T cell. The T cell then expresses a lineage-specific form of IL-1. This then activates the monocyte or macrophage into producing a beta lineage-specific cascade of signalling to initiate the required repair. This controls the first phase (G1) of mitosis and many other things. For many diseases that become chronically stuck in the first phase of cellular repair, this causes T cells to be continuously used up on cellular regeneration, and this helps stop T cells together with CD8+ and MHC class 1 ligands, from forming a ligand with B cells and expressing IL-10.

CD8+ and MHC class 1 would normally down regulate the first phase of the cell cycle and allow the second phase (G2), and apoptosis if required, to begin. The outcome of all this is that the adult cellular repair mechanism alters the immune system in the first phase to allow a quick repair without apoptosis, and alters it back to normal during the second phase of repair. Due to the lack of apoptosis in the first phase, this system can become mutagenic if it becomes chronic.

It is anticipated that a constant oestrogen supplementation in elderly women will not only help in PAD, but it will also help with some chronic autoimmune diseases, inflammatory-like conditions, sarcoma cancers, type 2 diabetes, cardiovascular disease, osteoporosis, some fibromyalgia, some neurological diseases such as MND/ALS, and general ageing.

I have recently proposed that approximately one in three women have avoided MND/ALS (Amyotrophic Lateral Sclerosis), because of their intake of the contraceptive pill and HRT therapy. Reference: www.als.net/forum/Default.aspx?g=posts&t=49561

At this stage I am limiting my comments to oestrogen and its effects in women. More research is required to determine whether it will assist males. Androgen secretion, testosterone levels and aromatase would require investigation as well as oestrogen levels and ratios.

Who will be most suitable for oestrogen supplementation?

Most beta lineage cellular regeneration diseases in women will be caused by a chronic muscle or tendon injury. As these injuries would mostly be considered minor, I would suggest checking the patient’s carbonic anhydrase III or myoglobin levels as these are sensitive tests, and will hopefully be able to detect small alterations. These tests are often used for suspected heart attack victims, but in these cases you will be looking for much smaller changes. Any test that can indicate chronic positive muscular damage will indicate the suitability of female patients that should respond to oestrogen supplementation to treat PAD. Question the patient if they have any chronic pain, even mild, in the common areas of fibromyalgia. If so, a T2 weighted index MRI scan can confirm if there is a chronic muscular injury in that area. It will show up as an opaque white spot whereas an acute muscular injury will show nothing.

Information for researchers wanting more detailed information.

A large part of understanding this proposal and its limitation of its effectiveness relies on an understanding of imprinted genes, or maternal or paternally expressed genes. You need to understand the role of imprinted genes in causing gender differences in disease.

Oestrogen supplementation levels should be kept low enough to down regulate insulin-like growth factor-2 (IGF-2), but not eliminate it entirely. If you eliminate all IGF-2 it will halt all beta lineage adult cellular regeneration throughout the body. This of course will cause unwanted side effects if the treatment is required long term.

It is recommended that oestrogen supplementation levels are low enough to require repeated cell cycles to clear and replace necrotic tissue, while still allowing minor injuries in other areas to heal. Aim at constant levels of oestrogen rather than high levels. This is not as critical in fast replacing skin cells (PAD), but it will be more relevant if trialling this on type 2 diabetes, and very relevant in bone cells (osteoporosis) or axons on motor neurons, which will both take a very long time to regenerate. Note: Most cases of osteoporosis occur in postmenopausal women when their oestrogen levels have traditionally dropped. Men have much lower levels of osteoporosis than women.

Although this hasn’t been proven yet, the lower numbers of women that get MND/ALS seem to fit this theory that constant oestrogen levels are very efficient at reducing MND/ALS in women. www.als.net/forum/Default.aspx?g=posts&t=49561 There are further references on these posts. When you read these references, you still have to connect the dots to understand where this proposal originated from.

Why is it important to know which cell lineage is involved?

There are three main cell lineages which are suggested to be called the alpha (α), beta (β) and gamma (γ) lineages. These three lineages will usually, but may not, be associated with a fourth lineage which involves endothelial cell repair.

The alpha lineage is very involved in cancer as the majority of cancers occur in this lineage. The alpha lineage involves epithelial cells which form the major organs of the body, the gastrointestinal tract and endocrine glands. This lineage is not involved in this proposal. This lineage follows or mimics the actions of the germ cell internal endoderm layer.

The beta lineage involves connective tissue or collagenous fibrous tissue of the extra cellular matrix, and includes muscles including smooth and heart muscle, tendons, bones, and probably white matter and cartilaginous/fatty/fibrous tissue. This is the main lineage involved in this proposal. This lineage follows or mimics the actions of the germ cell middle mesoderm layer.
The gamma lineage involves the brain and central and peripheral nervous system (CNS and PNS). This lineage follows or mimics the actions of the germ cell outer ectoderm layer. The following still has to be proven. The gamma lineage is integrally linked with the beta lineage. It is proposed that when the beta lineage repair process is in the first phase of regeneration, the gamma lineage cells (neurons, axons), cannot start regeneration, i.e. when beta lineage regeneration is expressing IGF-2, gamma lineage cells cannot start cellular regeneration. This would be the reason that neurons and axons have been so difficult to grow in vivo in human patients that have an active condition or disease involving the beta lineage.

It is postulated that hormones, and in this case oestradiol, will avoid the adult cell regeneration process and restart a foetal germ-cell-like growth process (mitosis) in the beta lineage.

Why suggest the monophasic oral contraceptive pill for the initial trial?

1. It is a proven harmless drug for women if taken short to medium term and generally is well tolerated. The minor side effects on initial use are well known. Small trials should start with middle age women, and then progress to elderly women.
2. The monophasic contraceptive pill is already developed and available in different strengths.
3. The monophasic version delivers a reasonably regular level of oestradiol. Any placebo pills could be discarded. Different strengths could be trialled.
4. Preliminary results for PAD should be evident with less than one month’s treatment.
5. Patients facing the possibility of gangrene or the loss of a leg would gladly commit to a trial using an approved contraceptive pill especially if they had previously used the pill.
6. It is envisaged that the contraceptive pill is used in the initial small trials to show efficacy. With encouraging results, it is expected that other reformulations of the drugs would follow, with normal major trials conducted on all of the possible beta lineage diseases. Repackaging and rebranding would follow.
7. Body builders use oestrogen to build muscle mass. The oestrogen triggers mitosis to create new muscle cells, and other beta lineage cells such as connective tissue.
8. A loss of oestradiol production leads to destabilized leaky micro vessels. This would permit chronic PAD in post-menopausal women, particularly if there was a concomitant chronic beta lineage injury or insult somewhere in the body.

Other possible existing treatments would include hormone replacement therapy (HRT) or oestrogen patches. Patches have the ability to deliver a constant dosage which is probably the preferred delivery method if a new treatment was being developed.

References:

1. Georges Mairet-Coello, Anna Tury and Emanuel DiCicco-Bloom. Insulin-Like Growth Factor-1 Promotes G1/S Cell Cycle Progression through Bidirectional Regulation of Cyclins and Cyclin-Dependent Kinase Inhibitors via the Phosphatidylinositol 3-Kinase/Akt Pathway in Developing Rat Cerebral Cortex. J. NEURO. SCI. 2009: 29(3): 775-788. DOI: 10.1523/JNEUROSCI. 1700-08.2009.
2. Olga V Glinskii, Tsghe W Abraha, James R Turk, Leona J Rubin, Virginia H Huxley and Vladislav V Glinsky. Micromuscular network remodelling in dura mater of ovariectomized pigs: role for angiopoietin-1 in estrogen-dependent control of vascular stability. Am J Physiol Heart Circ Physiol. 293:H1131-H1137, 2007.

---

David Hicks.

David,

Thanks for that information.

Measuring axon growth is probably like watching paint dry and not a pastime persued by many. It is obviously not rapid.

Irene's waistline I would say (But not within her hearing) would match your description. She was taking HRT until the day of her diagnosis which was 3 months after first symptoms but I would suspect at that time she would be fighting a losing battle. With the aid of Sodium Chlorite it might just make a difference and I can't see there is anything to lose by trying.

The doctor has prescribed for 3 months but you seem to think 1 month might be enough to show signs of improvements. I think Irene's mouth will be the easiest to tell as she is ordinarily not swallowing anything other than saliva .She does suffer constipation so colon improvements may be good. Her skin condition seems good and unchanged throughout.
I collect the prescription to day and we are due to resume OSC tomorrow so hopefully the twin pronged attack will make a difference.

I'm not sure about the the men on here - if it does work they may need to choose between ill health or improved health with breasts!!!

Thanks for your time.

John