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Multiple Sclerosis
Development

on Drug Development

Author: Prof. Jeremy David Block
Departmental
Head of Neurology & Neurological Research.
IAGIM Research Director & Chief Scientist of the Locum International Group
.
B.Sc. (Eng.). M.Sc. D. Pharm. Neuro-immuno Epidemiologist N.I.E. (IAGIM Research Institute)

INNOVATIVE & GENERIC DRUGS


PREVIOUS ARTICLE - THE THIRTEEN COMMANDMENTS

MULTIPLE SCLEROSIS EPIDEMIOLOGY
New Ideas and Concepts in Multiple Sclerosis from Epidemiology, Etiology to Epigenetics


IAGIM Drug Development Institute have currently undertaken a 10 to 15 year global initiative in the study of all five major types of Multiple Sclerosis covering diverse interdisciplinary fields of thyroid lymphocyte B-, T-cell selection, Virology (EBV, HH2-6-8 etc.), Blood CNS Barrier penetration, MHC, Protein folding chemistry, Immuno-molecular chemistry, Chronic and acute CNS inflammation sequence, Human Microbiota, Microbiota and CNS Connectivity, Cytokines & Chemokines role, Autoimmune scaring and lesion, in terms of neuro-immuno epidemiology, etiology, genetics (human genome) and epigenetics.

THE INTERNATIONAL GLIMER I, II & III MS STUDY (Ongoing 2010 -2025)
Prof. Jeremy D. BLOCK - Epidemiologist - Chief Scientist IAGIM Association and CEO LIGroup, IAGIM Association Chief Scientist, Head; Department of Neurology & Neurological Research, Neuro-Immuno Epidemiologist (N.I.E).

Multiple Sclerosis remains one of the most devastating illnesses of young adults, the commonest cause of disability after trauma, and one of the most enigmatic puzzles in Medicine. It is a complex and heterogeneous disease, in which both inflammation, de-myelination – removal of the ‘cables’ which insulate and increase speed of signal transmission in nerves – and nerve fiber degeneration occur in the brain and spinal cord. Repetitive immune attack against the myelin sheaths and oligodendrocytes, the cells that produce myelin, mark the first phase of disease in most patients. These events are termed relapses and cause temporary disability in themselves. This may be followed, or in some cases primarily established, by a slow cumulative degeneration of nerve axons, which leads to slow accumulation of disability – the secondary progressive phase. Bone marrow-derived stem cell transplantation may eventually replace some apoptotic neurons due to auto-immune exacerbation / attacks.

In Restorative Multiple Sclerosis Brain Repair has focused on attempts to repair the myelin loss, and attempts to generate new neurons as an assay to test reparative drugs, and possibly for transplantation. Oligodendrocyte precursor cells (OPC), Schwann cells – the myelin producing cells of peripheral nerves, olfactory ensheathing cells, and neural stem cells are studied using in vitro cell culture techniques and animal models. Various factors that prevent remyelination have been identified and there are also several growth factors that can stimulate the process. Further, has led the way in the trial of novel therapies (Campath-1H: alemtuzumab) that may not only reduce relapses in MS, but also prevent disability, and in the inception and development of international genome-wide association studies to find new susceptibility genes.

Prof. J. D. Block of IAGIM Drug Association and Founder and CEO of Locum International (Research) Group are beginning, via the International GLIMER I, II, and III MS epidemiological and epigenetic international research study, to unravel the past epidemiology research and development that could overturn the prevailing wisdom on the cause and progression of multiple sclerosis (MS) in men and women . Multiple Sclerosis in not only a debilitating neuro-degenerative disease that strikes predominately females at the peak of their childbearing life, but significantly, earlier in the lives, starting literally from birth as their immature immune system starts to develop during the critical pre-puberity ages of <1-3 and 3-6 years and onwards to puberty and then to child bearing and final to menopause. Although this disease strikes men as well, the incidence in men is significantly lower than females which is generally 2.5:1 and as high as 3:1 in the Atlantic Region of Canada (450+ per 100 000) compared to Cape Town or South Florida which are well under 10 or 50:100 000. Men normally get MS later (39-40 years) but more severely as PPMS (Primary Progressive MS). Well over 2.5+ million people worldwide, suffer from MS .

The question is why are the Canadian's and South New-Zealand numbers so high, when compared to the rest of the world. That conundrum is being unraveled by the intensive epidemiological epigenetics and geographical study covering most countries of the world. The answers are slowly unraveling and the results are both surprising, unexpected and require a total rethink of just exactly what multiple sclerosis, really is, today in 2015/6... Most of us got it wrong in the past. Highlighting a series of cascading effects and sequential serial triggers from birth - MS is a lifelong disease. It starts (postpartum) in very early child hood age with the developing immune system at birth and remains unseen and benign for close to less than two and sometimes as long as three decades before a detectable and recognizable exacerbation (attack).

This displays, as a two or three decade, cascade of triggering events that eventually culminate in the mid-twenties and early thirties in women with the second significant clinical event of MS. The first significant clinical event of MS is difficult to detect and identify as positive MS, as it is brief (only about 24+ hours) and the etiology is not clearly understood by the patient and equally poorly by the treating physician, who generally would not recognize the clinical event (exacerbation /attack) as RRMS. This first attack, at early child bearing age, will pass unnoticed as possibly an optical neuritis (remember the optic nerve is part of the CNS) not the PNS as the other 11 cranial nerves are classified. Alternatively, the young female in her prime will suffer a 24 hour gait or muscle problem, which could start as young as 18 - which few physicians are able to recognize as a clinical significant event. It is only at the second significant clinical event that both the patient, now in the early stages of MS can recognize that something serious is wrong, and an astute physician would concur.

The dormant or sub-clinical phase of MS has now passed, all the triggers have all fallen, and the neuro-degenerative CNS brain, optic nerve and spinal cord disease has displayed its "first, but really second" clinical life long debilitating symptoms. All the triggers in the two to three decade process or cascade have now tripped and the patient is truly sclerotic as per MRI/MRS normal white and gray matter scans show and oligoclonal bodies in the spinal fluid... So the question remains; What are these triggers and how do they fit into the almost two to three decade cascade or "domino effect" to use a well understood cliché'. There are several triggers in this early stage, but really it's mid to late stage RRMS that will, with added decades i.e. as time progresses, progress to SMS (Secondary MS) while PPMS (Primary Progressive) develop from onset mainly or predominantly in men, but luckily just less than 15% of RRMS will progress upwards - unlike in men. Their fate, when it starts, is significantly worse. It generally is faster, quicker and it is diagnosed as PPMS at age 40 or a smidgen later. This PPMS goes upwards, it's fairly constant and degeneration is faster and much more problematic. The International (ZAR-ISRAEL-USA-CANADIAN) GLIMER STUDY has separated the triggers over the life long decades up to the seventh or eight decade into a series of tipping points, such as, and in no particular order here - that comes later - the layered autoimmune development, GIT (70%) Lympho-leucocyte production, the critical GIT microbiota patient lifelong cycle and homeostatic role, (this microbiota homeostatic profile is really of critical importance), Bone Marrow B-Cells and Thyroid gland T-cells, The faulty thyroid quality control (TQC) producing a subset tiered range of passing and 'just passing' B- and T-cells (the whole group of them CD4+ CD8+ NKS and discussion of a further differentiating group of additional white blood cells and phagocytes (macrophages) that we will come to later).
The bottom line is that the thyroid gland rejects on or about 90% of the lymphocytes and leukocytes that the TQC
examines. Most of them are faulty, in fact almost all of them are, they are layered, flawed and have different faults - and the question really is, why?

That's a big question to answer and it has a lot of epigenetic background as highlighted by a 150 years of epidemiology especially unwrapping, teasing out and sorting the confounding conclusions reached, over the many decades of wrong or inaccurate conclusions. Confounding statistics, here too, plays an important role. In net effect, the thyroid only passes 10% of the presented white cells from the bone thyroid GIT and spleen etc. The approximate 10% of leuco-lymphocytes that pass the TQC
are much layered. Now that's an unusual medical term - these lymphocytes and leukocyte, white cells, have varying recognition and flagging abilities - all passing lymphocytes and leukocyte are not equal, they have different precognition abilities and some of them are poor and they flag badly, in fact some flag proteins very poorly indeed. These blood cells are improperly trained - really the equivalent 'dropouts' of the thyroid gland and these immature leuco-lymphocytes cannot really recognize own body protein - and that can cause an auto-immune disease, first inflammation and subsequent own-protein attack and the lymphocytes and leukocyte can't help it - they are not physiologically trained to do their job of recognizing own protein, effectively. They are kind of protein blind, in specific cases. (More of this later). Where the protein has a slight flaw due to a probable indel insertion then a 'pregnant protein' with a (bump) arises due to a one line or more than one line purine-pyrimidine miscoding. From here on a special CNS scenario is set up when a subset of leuco-lymphocytes (graded and layered) cross the CNS BBB by squeezing through the arteriole junction gaps and backing foot cells and enter randomly into the CNS NAWM (normal appearing white matter and also later the NAGM, normal appearing gray matter (detected by MRS - Magnetic Resonance Spectroscopy). At this moment of time it is a statistical entry (that is just a random entrance) but it soon progresses into a 'directed attack' concentrating in the pregnant (bumped) protein environment. The onset of a full scale, full blown autoimmune attack progresses in the classical style and sequence, i.e. B-cells, -> T-cell -> Mast cells -> Macrophages, CD4+, CD8+, and NK cells (inflammation, cellular disruption, myelin auto-immune attack, axon exposure and degradation with eventual scarring (sclerosed plaques) and finally lesions)

Now the question arises why are some of these lymphocytes and leukocyte (say 10% of those who pass, that's about 1%) are so poorly trained via the TQC system and how did they get to this point and why do they do their job so poorly i.e. attack normal basic myelin protein and other lipoprotein in MS as well as in a host of other autoimmune diseases (+/-81). Diseases such as RA, SLE, JD and MG (Rheumatoid arthritis, Systemic Lupus Erythematosis, Juvenile onset Diabetes (Type 1) and Myasthenia Gravis) all the way down to Stiff Persons Syndrome (Stickman's disease ) to mention a few. In order to answer this question we need to look at epigenetic, epidemiology, etiology and a smidgen of genetics and a large portion of the GIT Microbiota over an extended period of time (the early and second childhood decades) and later to mid childbearing and finally up to menopause. Men don't really have menopause, but mid-life crisis's - However, they have all the other tipping points in this extended, developing, ongoing persistent cascade with all the same sequential triggers.

Now the balance of the triggers that cause the cascade must be highlighted - early child viral immunization by mother (EBV and others), glandular fever, mononucleosis (kissing's disease), ancient adhesion proteins, (crossing the BBB), NAWM casual proximity, Oligodendrites and "their 40 feet" (one podium/many podia), DNA indels, (insertions deletions and repetitions, are mutation types), default protein folding small errors (affecting basic myelin protein in MS i.e. the pregnant {bump} protein ) -alternatively "the pea in the bed" or "pregnant proteins" analogy, MHC, random wrong site inflammation, B- and T-cells literally 'gone wild', (by analogy a hypothetical dog called 'Trigger' "digging up the garden (i.e. NAWM"), chemokines and cytokines production, messenger proteins - "don't kill the messenger syndrome", scaring and lesions, nodes of ranvier, axon degradation and eventual cleavage, and finally comparative autopsies of MS and non-MS patients and their surprising findings. The GLIMER STUDY has specifically excluded brain repair mechanisms and neuronal repair as in-depth epidemiology show this field is decades away (see foot notes below:)

This end Part One Part two of this ongoing review - will deal with the epigenetics and epidemiology triggers, such as early (a) EBV immunization, (b) Vit. D3 (24-25 dihydroxycholcalciferol), (c)
Normal sunlight exposure, (d) combination of a food symbiosis containing Vit. D3 and natural Sunlight to produce not less than 2000 IU's of equivalent D3 every day. Ingesting the right foods fully balanced and proportional. Not 400IU's per day but on average 2000 IU's of intrinsic and extrinsic Vit. D3 daily and in the proper daily ratios. The number of minutes of sunshine a young immune developing child and adult must be exposed to, is in the region of 22-35 min at day (weather depending), but certainly not 8 min. a day as is normal in Canada and much less in the Canadian Atlantic Region - eventually we will end with (e) Oligodendrites and their fatal unavoidable mutational mistakes (indels, insertions deletions and repetitions are simply a statistics numbers game) together with the (f) DNA indels and the (g) statistical probability of DNA mutations in synthesizing the amino-acids in basic myelin protein (and their surprising causes) affecting the 3.2+ and counting, billion lines of DNA code (purine and pyrimidine line CG/GC and AT/TA) and the global geographic regions variations as a function of epigenetic's and neuro-immuno epidemiology.

MS like polio is eventually a preventable disease, not quite yet at this time through vaccination, (i.e. via Retrospective-Prospective Didactic Vaccines (R.P.D.Vaccines) which are coming quite soon around the year 2020), but currently controllable through healthy lifestyles and careful and proper nutrition. The epigenics and etiology are becoming clearer, as the epidemiology dust over the past decades begins to settle. We need to take care of the developing first six years of life, in graded periods or age blocks, and develop a healthy immune system and keep it balanced and in a healthy homeostasis for future decades. Diet, sunlight and very early EBV inoculating by "Mom (viral and bacterial) Transfer Method" are three early trigger safeguards out of a possible twelve triggers, we need to protect and fully understand. Education in this parenting domain is important and critical - essential for a healthy life from cradle to grave. We are now understanding the basic underlying etiology, how and when MS all starts - so many years ago in very early days of childhood (in-fact it's really immediate postnatal), even C-Sections are discouraged as they affect the gastric human microbiota and other 'all-orifice-human-microbiota' and thus affecting the immune developing system significantly (As said 'about Vegas' what happens in the GIT Human Microbiota does not stay in the Human GI Tract [i.e. colon etc.]) and for sometime now, we know - how it (MS) all ends...


Prof. Jeremy David Block B.Sc., (Engineering, ZAR. SANA.), M.Sc. (Micro/Stats (U. of WC), D. Pharm., (Wits ZAR), (Neuro-Immuno Epidemiologist (N.I.E.) (LIG-IAGIM)
Part Two 2015/6. - Total Parts 20 - Pages 210).

Background: Prof. Jeremy D. Block served for the duration of the development of COP 1 as a senior medical/pharmaceutical researcher and part of the Teva COP 1 innovative research team in the early nineties that rapidly developed Teva's first MS immuno-modulating drug Glatiramer Acetate (CopaxoneTM). As Chief Scientist as well as Teva Group Scientific Research Auditor, and by touching each and every part of Teva's overall global scientific team, Teva rapidly attained New Drug Registration with the FDA under Prof. J. D. Block scientific and technical guidance and regulatory department training and systemic overviews and audits.

Note * ISRAEL Israeli Jews have a prevalence of up to 62 per 100,000, but Christians (35 per 100,000), Moslem Arabs (15), Druze (11), and Bedouins (17) have lower rates (Alter et al 2006). Genetically similar immigrants have half the rate of native-born Jews, suggesting an environmental factor. Other groups also have a significantly lower incidence of multiple sclerosis (Caucasians) Hispanics Latino's black African Americans, Asians African Natives, Inuits, SWA bushman, and Romani Gypsies (almost zero)).

FOOTNOTES
Brain Repair mechanisms - Why does the brain need repairing?
Most types of neurological damage lead to permanent disability. People with spinal injuries never recover from their paralysis and loss of sensation, as an example those suffering from Parkinson’s disease will never recover from the condition and always be reliant on medicines. Patients with multiple sclerosis never recover fully from their lesions. This is because the brain and spinal cord lack the ability to heal themselves after injury. Many nerve fibers in the brain and spinal cord are insulated by myelin, which is a sheath formed by glial cells called oligodendrocytes. If this insulating sheath is removed, the nerve fibers cannot conduct nervous impulses.
This happens particularly in multiple sclerosis. In this disease an autoimmune process kills oligodendrocytes (myelin-forming cells) in small patches of the brain and spinal cord, leaving the exposed nerve fibers uninsulated and therefore poor- or non-conducting. These patches, known as plaques, are usually only a few millimeters in size, but they can occur frequently anywhere in the brain or spinal cord. The plaques do not generally repair themselves. The result is small regions in which the nerve fibers do not conduct. These give symptoms which depend on where they are, and the function of the nerve fibers that are affected.


BRAIN REPAIR
Repairing the structure of the brain and spinal cord Replacing lost neurons (1) Where neurons are permanently lost, there are two potential ways of replacing them. The first is to transplant equivalent neurons taken from a donor brain or spinal cord. The second is to persuade primitive stem cells, which are present in the adult brain or can be transplanted, to turn into new neurons. Neural transplantation. If a group of neurons are lost, an obvious possibility is to transplant new neurons in their place. This is particularly attractive in diseases such as Parkinson’s disease, in which the lost neurons are all in a small restricted site.
Successful neuronal transplantation has not been achieved using neurons from adult donors. However, if neurons are taken from embryos of just the right age, they will survive transplantation. In addition they will grow nerve fibers into the host brain and make functional synaptic connections. In animal models of Parkinson’s disease this cures most of the symptoms of the disease. This has led to several trials of neuronal transplantation using embryonic tissue for human patients with Parkinson’s disease. In almost all these trials the patients have had their disease partially corrected, but in no case has there been complete recovery.
Methods for improving the results of these operations are ongoing.
Normal Status. - The substantia nigra is intact, and its nerve fibers connect to the striatum.
Parkinson’s disease. - Most of the neurons in the substantia nigra have died, and few nerve fibers remain to connect to the striatum. A graft of embryonic substantia nigra has been placed in the striatum. It sends out nerve fibers that innervate the striatum and bring back lost neurological function.

BLOCKING SIGNAL TRANSMISSION -
How is nerve fiber conduction blocked? Many nerve fibers in the brain and spinal cord are insulated by myelin, which is a sheath formed by glial cells called oligodendrocytes. If this insulating sheath is removed, the nerve fibers cannot conduct nervous impulses. This happens particularly in multiple sclerosis. In this disease an autoimmune process kills oligodendrocytes (myelin-forming cells) in small patches of the brain and spinal cord, leaving the nerve fibers uninsulated and therefore non-conducting.

PLAQUES
These patches, known as plaques, are usually only a few millimeters in size, but they can occur frequently anywhere in the brain or spinal cord. The plaques do not generally repair themselves. The result is small regions in which the nerve fibers do not conduct. These give symptoms which depend on where they are, and the function of the nerve fibers that are affected.

NEURONAL DAMAGE

Recall that the three main causes of loss of function after damage to the nervous systems are: (a) loss of neurons, (b) cutting of axons and (c) loss of insulation on axons. None of these deficits heals spontaneously. Lost neurons are not replaced. Neurons are created during embryonic development, but after that time we have almost no ability to make new ones. Thus, when large numbers of neurons are killed they cannot be replaced, and the disability that results from their loss is permanent.

Cut nerve fibers also cannot regenerate. In order to restore the function of cut nerve fibers, they need to be able to re-grow from the site of the cut back to their original connection site. Nerve fibers in the brain and spinal cord are completely unable to regenerate. Therefore nerve fibers cut in the spinal cord as a result of a cord injury will never redraw, and people with cord injuries will be paralyzed for life. Lost insulating myelin is not fully replaced.


Oligodendrocytes Apoptosis
When the oligodendrocytes that form myelin are lost (die) as a result of multiple sclerosis, the brain and spinal cord have a very limited ability to replace them. Therefore many of the multiple sclerosis plaques never become re-myelinated. This means that the nerve fibers that pass through these plaques can never conduct nerve impulses normally, and eventually many of these demyelinated nerve fibers will die.
Multiple Sclerosis remains one of the most devastating illnesses of young adults, the commonest cause of disability after trauma, and one of the most enigmatic puzzles in Medicine. It is a complex and heterogeneous disease, in which both inflammation, demyelination – removal of the ‘cables’ which insulate and increase speed of signal transmission in nerves – and nerve fiber degeneration occur in the brain and spinal cord. Repetitive immune attack against the myelin sheaths and oligodendrocytes, the cells that produce myelin, mark the first phase of disease in most patients. These events are termed relapses and cause temporary disability in themselves. This may be followed, or in some cases primarily established, by a slow cumulative degeneration of nerve axons, which leads to slow accumulation of disability – the secondary progressive phase.

Work at brain repair is decades away, has focused on attempts to repair the myelin loss, and attempts to generate new neurons as an assay to test reparative drugs, and possibly for transplantation. Oligodendrocyte precursor cells (OPC), Schwann cells – the myelin producing cells of peripheral nerves, olfactory ensheathing cells, and neural stem cells are studied using in vitro cell culture techniques and animal models. Various factors that prevent remyelination have been identified and there are also several growth factors that can stimulate the process.

Further, trials of novel therapies (Campath-1H: alemtuzumab) that may not only
reduce relapses in MS, but also prevent disability, and in the inception and development of international genome-wide association studies to find new susceptibility genes.

The complete article of the month is available at the
COPYRIGHT C 2016 - 2017


M/S Article: A total of 20 chapters will be placed online, progressive getting more and more detailed and with a greater degree of complexity and modernity, right up to 2010/2025 state-of-the-art know-how and databases. It is the intention of the GLIMER STUDY I, II & III to publish the entire FIFTEEN year study on-line - free to all mankind and all MS sufferers.
MS R&D CHAPTERS - 1 - 2 - 3 - 4 - 5 - 6 - 7 - 8 - 9 - 1 0 - 11 - 12 - 13 - 14 - 15 - 15 - 16 - 17 - 18 - 19 - 20

Human Genes
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 M


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