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    Regenetek’s Combination Stem Cell and Vascular Therapy

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Combination Therapy

Combination Therapy for MS Explained

Background

MS is a chronic inflammatory disease of an autoimmune source that randomly affects the central nervous system (brain, spinal cord, optic nerves)  where the myelin sheaths that act as  insulation for nerve cells in the brain and spinal cord are damaged by the disease process. This damage disrupts the ability of parts of the nervous system to communicate via the neural pathways, resulting in an array of symptoms, including physical, mental, and often psychiatric problems. Almost every MS patient is affected by their disease a little differently and symptoms are determined by the positioning and area size of lesions that occur within the nervous system as a result of the disease process.

Current Medications for MS only Modify Symptoms and are of  Uncertain Value Despite High Cost

The current disease-modifying pharmacological approaches to treatment (DMTs) do not recognize the disease process by which these lesion or plaque sites form or that they need to be repaired; nor are they specifically formulated to either target those areas or effect repair. In fact, medications have been proven not to alter the course of the disease and are only intended to modify disease symptoms. Given the cost of the medications and their side-effects, it remains a curiosity that in the face clear warnings from the American Academy of Neurology that many neurologists continue to prescribe interferon-beta (glatiramer acetate) as a matter of course to MS patients. The four newly-licenced drugs of suppressive immunomodulatory class that are meant to replace the last generation of medications for MS, also claim efficacy and were licenced based entirely on evidence produced by the drug companies. It may take many years for watchdog groups such as the Cochrane Collaboration to refute evidence, but they have already produced a warning: ‘…that (drug company) conclusions (regarding these new drugs) do not take into account studies of high enough quality, treatment complications beyond two years, compliance data, (or) reformulation of the investigational drugs or physician experience. There were no adjustments for the era of the study or differing baseline characteristics of the patients at study entry.”

Ethical Considerations for this Research

Regenetek Research Inc. is conducting research in a Case Study Series  under the terms of Institutional Review Board sanction (with IRB approval through the DCG (India), IECP, (India), ICMR (India) (IRB File No. ECR/44/IECP/27/2011), and as of March 16, 2014, Institutional Review Board approval has been granted by the US-based International Cell Surgical Society (ICSS) (Approval # ICSS-2014-004), with patients who qualify studied for a period of 5-years.  The study entitled ‘Intravenous and Intrathecal Implantation of Adult Autologous Stem Cells for Patients with Multiple Sclerosis and Other Neurodegenerative Diseases’ is an investigation of a novel, sequenced therapeutic strategy that considers both the vasculature and central nervous system in a treatment with adult autologous stem cells (cells taken from the patient). Based on what has been established as evidence in previous investigations into neurodegenerative diseases through clinical trials, this protocol was developed over several years- 2009 through 2011. The study was approved on June 16, 2011 by the IECP and patient therapies began in August, 2011. The clinicians and physicians involved in this research are members of, and abide by the regulations of the International Cellular Medicine Society,  the only medical association in the world that has published a comprehensive set guidelines for the practice of stem cell medicine. As guaranteed by the Declaration of Helsinki (Article 37) and Belmont to which Canada and the United States of America are signatories, the professional group administering this study believes that an informed patient has a right to access new and innovative treatment options that are under study.  In consultation with a qualified physician, a patient must be empowered to make an informed healthcare decision. Furthermore healthcare professionals world-wide are entitled to abide by the tenets of these World Medical Association doctrines (statement of ethical principles for all medical practice and research) and this right supersedes the power of medical boards, or governing colleges to mandate compliance of members where the two are in conflict.

The study investigates the safety and efficacy of the therapeutic repair mechanisms of stem cells in blood brain barrier disruption, a pathological occurrence common in multiple sclerosis and other neurodegenerative diseases such as ALS, Alzheimer’s and Parkinson’s Disease. With the availability of new in vivo measurement and imaging techniques, Dr. Broeska, as Principal Investigator and his research group have been studying relationships between abnormal vascular and neural pathology in the diseased central nervous system. As a result of a review of the data that has been collected over the past several years, Broeska believes that there is a very fine balance between health and disease and he is attempting to recognize events and/or conditions that foreshadow the change from the healthful state to the disease state.

In his study, Broeska is uniquely investigating the cascade of events that lead to microglial activation in the diseased brain, subsequent inflammation, neuronal compromise and ultimately, symptomatic neurologic entities as a result of vascular injury; and how both the vascular and neurologic deficits are improved both immediately and continuously upon super-selectively directed infusions of specific types of autologous mesenchymal stem cells into the areas of neuronal injury/compromise. In studying a precise sequence of interventions, his ultimate goal is not only to correctly identify the targets for therapeutic intervention, but to permanently resolve the disease state.

Novel Approach in a Sequenced Protocol

To accomplish this, Regenetek Research has taken a novel approach that has had a significant and real effect on the disease. Depending on the stage of the disease, significant effect would mean halting the disease process and/or repairing the damage to the nervous system. Understanding the disease trigger is the first step to developing an effective treatment strategy and to do this, we have used existing clinical studies that have determined the cause of chronic inflammation in the brain.

The Regenetek study recognizes that MS is an autoimmune CNS specific disorder. An analysis of spinal fluid reveals certain proteins associated with both the presence of, and the current intensity of the disease activity. A direct link can be made between the dysfunction in MS which is either cognitive, or manifests itself in the form of pathological degrees of weakness, spasticity, bowel and bladder dysfunction as well as paralysis that is a result of spinal cord disease.

Uniquely, we have selected a type of autologous mesenchymal stem cell (MSC) that has been isolated and characterized from a population of marrow-derived adult cells. The method of treatment starts with a small amount of stem cells within the patient’s own marrow sample that are harvested and separated, grown and expanded in a laboratory under proprietary protocols. To confirm that this methodology is sound, two other US studies at Tisch in New York and Cleveland Clinic are using similar cells.

But this is where the Regenetek study makes a distinct departure from the other two studies, making our therapeutic protocol entirely unique. Unlike the other two clinical trials mentioned, our study hypothesis postulates that both the vasculature and the central nervous system of the patient must be considered in any effective treatment of MS. Recovery combination considerations must include a synthesis of certain adult stem cells involving growth factors for stem cell proliferation, inhibition of glial scar tissue, and stem cell infusion strategies; but also inhibition of neurotoxin leakage through the vascular system across the blood brain barrier. Yes, that’s making a vascular association with the disease, but not specifically the ‘Zamboni hypothesis’ that postulated cervical veins may be the disease trigger for MS. Our own research has detected measurably significant neurotoxic leakage through disrupted venules within the central nervous system correlating to the location of microglial clusters, compared to cells at adjacent perivascular areas that exhibit normal cell population density. A recent California study has identified this neurotoxin as fibrinogen, a clotting protein. The drawing below depicts the disease mechanism. Experimental Autoimmune Encephalomyelitis (EAE), replicates the mechanism by which patients have an MS attack. In MS, this happens deep within the cell-bed of the brain and is  informative as to the disease trigger. The Combination Therapy protocol is the ONLY therapeutic intervention world-wide that has ever specifically addressed the underlying cause of the disease.

Fibrinogen

As can be seen in the evolution of the disease over the three stages, once increased vascular permeability has been established in the MS brain and leakage occurs, an autoimmune response is triggered, which results in leukocyte extravasation through the extracellular matrix towards the site of inflammation. Fibrinogen induces release of reactive oxygen species (ROS) in microglia and its signaling through CD11b/CD18 is required for the formation of perivascular microglial clusters and subsequent axonal damage. Observation over time reveals that leakage is sustained at these sites resulting in persistent axonal destruction and subsequent onset of neurological signs. These findings strongly support that fibrinogen-induced microglial clustering around the vascular weaknesses serves as a mechanism to enable lesion formation and focal axonal damage. The photos below are actual 2-photon microscopic images upon which the drawing above was made.

MS microglial response to fibrin protein leakage across BBB

This short video will concern itself with Phase 1, Part 3 of the overall Combination Therapy protocol, which illustrates a novel technique of percutaneous cannulation and infusion of mesenchymal stem cells (MSCs) into extra-cranial veins. In this case, cannulation involves inserting a catheter into a patient’s internal jugular vein(s) (IJV) so that MSCs can be infused directly into the patient’s bloodstream. Administration of intravenous fluids is consistent with the method of implementing a small bore balloon-tipped catheter as described in Regenetek’s research protocol for cell infusion. Specifically, reversal of extra-cranial venous flow through timed-surge induction of hemodynamics simultaneous to stem cell infusion which allows for highly-controlled diffusion of cells towards the central nervous system, including venules and microvenules.

Reverse extracranial flow      Reverse extracranial flow2

Neurodegenerative diseases such as MS are characterized by disruption of the homeostatic balance within the venous vasculature of the central nervous system (CNS), axonal damage and demyelination. Recent analyses of pre-demyelinating MS lesions identifies blood-brain barrier (BBB) disruption and activation of microglia, the resident immune cells in the CNS, as the earliest pathological signs in otherwise normal appearing white matter. In fact, the most characteristic feature of microglia cells is their rapid activation in response to even minor pathological changes in the CNS. Microglial activation is a key factor in the defence of the neural parenchyma against inflammation, trauma, ischemia and neurodegeneration.

Fibrin deposition in active demyelinating MS lesions corresponds with increased inflammatory activity and microglial activation. If a consequence of BBB leakage in MS is the extravasation of plasma fibrinogen that results in the local deposition of perivascular fibrin matrices, as a first step to overcoming the source of the leakage, it is essential to develop a technique to halt that occurrence. In cases of chronic instability and inflammation via disease mechanisms, microglia may also transform into cytotoxic cells, exacerbating the response.

Current approved therapies have not been successful for reducing the progression of disability. Medications, especially suppressive immunomodulators, while commonly prescribed, do not respect the disease etiology and therefore targeted drug therapies are inadequate. Furthermore, whether or not clinical interventionists target disease triggers, traditional, non-interventional surgical options are not possible deep within the brain. Stem cells when infused in the manner described, have the ability to suffuse every part of the brain from the venous, or outflow side of the CNS and this has formed a rational basis for targeted intervention on glial reactions to injuries in the CNS and re-creating homeostatic balance.

Once directed to the smaller venules of the CNS, stem cells are unaffected by flow dynamics but are stimulated instead through chemotaxis, that is, the natural ability for stem cells to adhere, conduct surveillance and mobilize towards areas of disease identified  by the signalling factors in the vasculature. Venules and micro-venules that demonstrate evidence of trauma are thinner and endothelial cell walls are observed to be extremely porous. Once located at the site of this vascular pathology and if in present in therapeutic numbers, MSCs manifest the characteristic properties of stem cells; self-renewal and differentiation including non-thrombogenic properties that act to effectively regenerate normal vascular tissue to stop leakage from occurring and the subsequent cascade of pathological events.

Addressing blood brain barrier disruption of vasculature has the following advantages over other types of interventions:

  1. Cause of the disease is addressed
  2. Directed delivery of stem cells allows for greater efficiency
  3. Requirement for a decreased total quantity of cells
  4. Provides venous access for adjunctive techniques such as venoplasty
  5. Safe with virtually no chance of intracranial bleeding or hemorrhage
  6. Probability of decreased incidence of recurrent neurologic events
  7. No side-effects analogous to drug therapies
  8. Probability of only single intervention required
  9. Improved quality of life

 

Combination Therapy is a Sequence of Minimally Invasive Procedures

This is a Case Study Series. There will be no randomization in this study as it is not appropriate to a credible or ethical study design. If study data is compared to natural history of the disease in MS patients (cohort), outcomes over time are already well-known. All subjects who are determined to be eligible for the study treatment will receive the Combination Therapy protocol including cervical venoplasty if indicated and/or cervical vein flow management followed by multiple infusions of autologous MS cells, some cultured as per the protocol, and expanded to clinical numbers ex vivo. Prior to all procedures, a neurologist will establish a baseline for all patients’ general health and disease condition via medical record and clinical evaluation. A Consent Form is necessary for patients to provide bone-marrow derived cells, as well as for stem cell infusion. The procedures the subject will undergo are as follows:

  • Aspiration of autologous bone marrow
  • Aspiration of cerebrospinal fluid obtained via lumbar puncture
  • Cervical vein flow management via catheterization
  • Stem cell catheter infusion into extra cranial and cervical veins
  • Stem cell infusion into spinal canal via lumbar puncture
  • Follow-up diagnostic imaging

 

Sequential Procedure for Reversal of Extra-cranial Venous Flow through Timed-surge Induction of Hemodynamics

Patients with Multiple Sclerosis generally demonstrate evidence of a disease known as chronic cerebrospinal venous insufficiency (CCSVI), and are candidates for a sequence of therapies with stem cells that infuse these cells into the cervical neck veins post-venoplasty via catheterization. Whether or not this blockage exists, as indicated in the detailed explanation above, it is necessary to induce retrograde flow dynamics. This incorporates:

  • Catheter Venography
  • Minimally invasive balloon venoplasty
  • Stem cell infusion via catheter into cervical and extracranial veins as indicated

 

Required Procedures for Combination Therapy:

  • Aspiration of bone marrow will be done only once and will take approximately two hours including the second procedure which is the aspiration of CSF.  The amount of bone marrow as determined appropriate for each patient, aspirated by being drawn into a syringe.
  • Cerebrospinal fluid taken via lumbar puncture will be aspirated once. The amount drawn will be appropriate to the size and weight of the patient as determined by the neurologist.
  • Patients who undergo autologous stem cell transplants in sequence over the next weeks will receive the appropriate number of stem cells implanted into both their cervical venous flow via femoral vein cannulation and cerebrospinal fluid through lumbar cannulation. Autologous stem cells and the CSF transporter fluid allow the cells to locate and remain at the site of injury.

 

Discussion

From the consistent response of patients to date, it is likely that the introduction and presence of certain types of stem cells (MSCs) in the immediate diseased environment in the CNS respond to the release of Reactive Oxygen Species (ROS), which have previously transformed the white matter area into a toxic environment with resultant chronic inflammation of tissue. When inflammation occurs, immune cells at the site of inflammation produce inflammatory mediators called cytokines. In response to these cytokines, which act as chemical messengers, the population of mesenchymal stem cells, newly introduced through the venous system of the CNS, are mobilized in therapeutic numbers and become stimulated to produce chemokines and nitric oxide. The chemokines function to attract T cells which migrate toward to the MSCs, which are now releasing nitric oxide to suppress their autoimmune function, thus halting the disease process. Subsequent to the stabilization of the environment, stem cells then differentiate into endothelial tissue to heal damaged, leaking tissue within the venous vasculature. In the second part of the protocol, newly infused MSCs (true stem cells) infused into the CNS via lumbar puncture, allow myelin repair, restoring nerve transmission and subsequent functional recovery for the patient. Trial evidence further indicates that stem cells transported in this mixture via the spinal canal allow deeper penetration into the tissues and the cellular structures of the brain, effecting increased healing of all affected tissue. Evidence has been established that typical disease symptoms diminish soon after selective infusion of the expanded cell culture in therapeutic numbers.

 

The Past is Prologue- The Lancet Publication is NOT the Final Word on Investigation of MS – CCSVI Link

Vascular dysfunction in MS clearly exists. As stated, the anomalous pathology in the cervical veins of an MS patient may only be representative of the abnormal pathology throughout the entire venous system which chronically impairs venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) was coined. And by now it is apparent that the significant drainage impairment caused by occluded jugular veins creates significant and measurable hemodynamic pressure on the central nervous system which exacerbates the disease process. This may not matter for persons not predisposed or preconditioned to vascular malformations in the central nervous system, but thinner-walled venous vessels can buckle or shear for several reasons, including high blood pressure, low axial tension or trauma. In such cases, at the level of the white matter in the CNS, this intensified pressure within intra and extra-cranial veins, venules and micro-venules increases fibrin leakage across the blood-brain barrier contributing to axonal damage in neuroinflammatory disease. Additional clinical evidence implies that some types of focal lesions are ischemic in origin, possibly associating reduced white matter perfusion with cognitive dysfunction. All of this clinical evidence does not exactly lend itself to CCSVI as having no role in MS. The vascular association is clear, but to what extent may occluded cervical veins be correlated to MS? Traboulsee, et al, say it’s not possible. But the problem with ‘not possible’ is that OUR research hypothesis exploits the inverted flow as a result of the pathology in the IJVs to treat the CAUSE of the pathological diffusion of neurotoxins through the BBB. A clear link.

In all science, prior research only inspires deeper and more complex questions that demand further research. When Paolo Zamboni came up with a fresh and original idea to explain an anomalous observation about a disease process, hopeful expectations led to unfortunate consequences for many MS patients who invested heavily in their intuition prior to scientific evidence being produced for his theory. As a result of social media, many MS patients succumbed to near-irresistible peer pressure, and flew to far-off lands when medical colleges would not allow cervical venous angioplasties to be performed in local jurisdictions. Desperate and hopeful patients were encouraged by paid patient advocates and seemingly credible profiteer physicians who were somehow ethically comfortable performing unproven therapies outside of research protocols even though the experimental procedures lacked SOPs, proper institutional oversight, informed patient consent, vulnerable subjects criteria, protocols, quality controls, monitoring and especially data monitoring, CRFs, and were absent of the ability to report significant Adverse Events (of which there have been many for the so-called ‘liberation therapy’).

Few MS patients could avoid the mainstream media hype and most joined one social group or another on web-connected social media. Seeing visual evidence of temporary improvements in select patients who had the vein-expanding therapy early, on sites such as YouTube, many patients began clamoring for, even holding public rallies and DEMANDING of their politicians that the ‘liberation therapy’ venous angioplasty medical procedure should be a ‘human right’ and that their medical plans needed to fund it. Some politicians got on-board especially in areas where the prevalence of the disease was high. However, as the procedure was experimental and not previously recognized as a pathophysiological condition that had no medical basis for treatment, insurance funds did not cover it. So patients spent precious and sparse personal resources on having interventional cervical vein therapy that didn’t work in the end, but for which those certain controversial doctors gladly accepted payments from desperate patients, even though they knew that balloon-expanded veins could not maintain patency and would eventually return to their anomalous occluded shape with additional internal injury as a result of over-treatment, but also lack of care, lack of experience of the operator, and/or lack of written protocols and standards for venous angioplasty. Many patients were treated multiple times by the same doctors, until the jugular veins were so completely congested with scar tissue, they would never accommodate flow again.

Because so much was at stake for both patients and the medical establishment as to what the investigation of CCSVI would eventually produce, hastily conceived clinical trials were organized. Evidence of efficacy of Zamboni’s hypothesis was supposed to be established, but clear biases also altered the manner in which studies were done.

In the end, (October 9, 2013)  the Lancet-published research by Anthony L Traboulsee, et al, (“Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study”) and the subsequent Article by Paul Friedemann entitled: “Chronic cerebrospinal venous insufficiency in multiple sclerosis: the final curtain” regarding the association between CCSVI and MS reads more like a joyful and collective sigh of relief by the neurologist community than a clinical study (I have reviewed the study and have noted several significant biases which I will comment on in a later article).

In any case, the evidence, as meagre as it is, was in…and this was thought to be the last word. Unfortunately the several doctors who performed thousands of commercial venoplasty therapies on MS patients as medical tourism over the years fell silent. How did this reconcile with the bold claims on their websites about efficacy of treatment and client satisfaction through patient testimony? If ANYONE could have defended venous angioplasty on behalf of MS patients, it would have been this group of doctors. They said nothing in their defense because they contributed not a whit of actual evidence nor meaningful observation as to the efficacy of the ‘liberation therapy’. From the beginning, they absolutely knew that their time was limited as even the most perfunctory review of a small sample MS patients, if investigated, would put them out of business the way they were practicing their medicine. In reality, these Interventional Radiologists were little more than opportunistic bystanders who just happened to be there outside the bank when the explosion blew the money all over the street and all they had to do was bend over and pick it up. Had these doctors really cared about collecting data and following up with patients, not only would lives have been saved without the iatrogenic injuries that have occurred in veins of hundreds of patients, but other more helpful observations about CCSVI could have been made much sooner and informed us as to new more useful associations in vascular MS. Adjunctive therapies could have been started earlier and more-widely studied with greater rigor.

The research we are doing here embraces the fact that in science, there is NEVER a last word…or a ‘final curtain’ as The Lancet proclaims about CCSVI and the vascular association to MS. It is surprising that a publication such as The Lancet, which has published for almost 200 years, has printed an article headline that aims to ‘close the book’ on a particular aspect of medicine. If there’s one scientific group that should appreciate and celebrate the fact that as our knowledge expands, so too does our awareness of what we don’t yet understand, it must be The Lancet who started their publication at a time when blood-letting was the most common medical practice performed by physicians in the western world.

As long as unproven medicine is performed safely, ethically, with informed consent of the patient and under purview of an oversight board with the objective of producing data that will lead to evidence, it must be encouraged and supported. This is how medical research has traditionally been done and there are many practical and ethical study designs despite the barriers to entry that are imposed on good research by ethical investigators in these days of giant corporate interests.

 

APPLICATION AND QUALIFICATION FOR RESEARCH STUDY

Several sites world-wide are now studying the Combination Therapy in affiliation with Regenetek Research but only one clinic is currently performing the actual protocol. Due to expansion of qualification criteria, patients with diagnosed cases of MS qualify at almost any stage of their diagnosed illness unless they have other exclusionary factors (such as cancer, chronic diseases, etc). It is within the purview of the study to examine outcomes in all stages of the disease. This includes disability levels of the disease from 2.0 through to 9.0 EDSS. Applicants must send a clinical diagnosis of MS and submit their most recent chart notes. Topographical MRI scans are most useful especially in a series over time. Certain medications must be discontinued for stem cells to work and there would be a ‘washout’ period for these medications to leave the patient’s body.

Applicants who qualify will be asked to participate in a long-term study with follow-up features that are a requirement of entry into the program. Case-controlled studies on each patient will build a body of data that will be extended into a prospective cohort study. The researchers and the doctors are following International Cellular Medicine Society (ICMS) guidelines and the study has been undertaken under the hospital board IRB as well as ICMR regulations. The study has been further undertaken through the newly affirmed Article 37 of the Declaration of Helsinki as sponsored by the World Medical Association (WMA). This is not a Canadian or an American study and is funded partially by the patients themselves. All patients must give their informed consent. Patients must agree to be studied for a 5-year period. Data collected at the clinic site before during and after procedures is extensive and over a dozen medical specialties are involved in any single patient therapy.

In the the first quarter of 2014, all patients having undergone the therapy will be given new web-based Medical Trial software and each patient will have their own website log-in area where they can see a chart of their progress and review their changes. Since the clinic now has a world-wide patient base, sites will be available in different languages. Patients will be asked to log in at defined intervals for a period of 3 to 5 years to answer questions about their recovery and outcomes or to chart or communicate adverse events. All patients will have their own functional dashboards where their entered survey results over time will be converted to graphs that the patient can use for review or even print their outcomes. Scans, videos, and other data are all uploadable and make up part of the patient record. Individual patient record data and all records submitted will remain in the patient’s file for as long as the patient wishes. (The database is secure and complies with HIPAA (Public Law 104-191, 1996) security and privacy regulations as ‘protected health information’ and PHI database (HIPAA/EDI Provision, Oct 16, 2003). Electronic protected health information (EPHI) security rules state that any electronic communication transmissions containing PHI information must be encrypted and protected from intrusion).

All data from all of the patients will be aggregated into a larger Prospective Cohort Study that will attempt to provide the efficacy of the ‘combination therapy’ method over ‘liberation therapy’ alone, or stem cell injections alone.

The Program is limited in number of applicants. To apply for the Combination Therapy protocol, you may go the ‘Application Forms’ tab on the Homepage of this site. For more information on the Combination Therapy protocol you may send an email to apply@ccsviclinic.ca or call the toll free line at 888-468-1554.

 

Written by Doug Broeska

Doug Broeska is a PhD Medical Researcher and CEO of Regenetek Inc, a Canadian Biotech Research firm working with several hospitals and clinics world-wide to develop medical procedural protocols for neurodegenerative disease management.