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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 4  |  Page : 176-180

Neurologic Stem Cell Treatment Study (NEST) using bone marrow derived stem cells for the treatment of neurological disorders and injuries: study protocol for a nonrandomized efficacy trial


1 The Healing Institute, Margate, FL, USA
2 MD Stem Cells, Westport, CT, USA

Date of Web Publication30-Dec-2016

Correspondence Address:
Steven Levy
MD Stem Cells, Westport, CT
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-5658.196984

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  Abstract 

Background: A large number of approximately 600 known neurological diseases have no or limited medical interventions; many treatments are temporizing or only marginally effective and have changed little over decades. The Neurologic Stem Cell Treatment Study (NEST) utilizes bone marrow derived stem cells (BMSCs) for neurological diseases and injuries to nervous tissue.
Methods/Design: Administration of BMSCs is an established approach for the treatment of neurological diseases and injury with its effectiveness verified in the pre-clinical and clinical studies. BMSCs and the associated bone marrow fraction are posited to have a number of different mechanisms by which they may potentially improve neurological function. The circumventricular organs which lie in the wall of the third ventricle are noteworthy for a minimized or absent blood-brain barrier (BBB) facilitating entry of intravenously provided BMSCs. There is documentation in the literature that intranasal delivery of BMSCs may follow the pathways of the trigeminal nerves, facilitating their entry into the pons, brain parenchyma and cerebral spinal fluid (CSF) for effects on the CNS. The NEST is an open label, non-randomized, efficacy study with two arms. Arm 1 consists of intravenous autologous BMSCs alone; Arm 2 combines intravenous with intranasal application of BMSCs to the lower 1/3 of the nasal mucosa. There will be a total of 300 patients in the study. Endpoints include at least a 10% improvement in neurological function.
Discussion: There have been a number of preclinical studies establishing the utility of intravenous and intranasal methods in providing access to the CNS for certain drugs, proteins and cellular elements. Preclinical and clinical studies utilizing BMSCs have shown positive effects in various neurological diseases. It is anticipated that combining these two administration methods for BMSCs delivery to the brain may provide a greater therapeutic response.
Trial registration: ClinicalTrials.gov identifier NCT02795052; registered on June 6, 2016.
Ethics: This study protocol has been Institutional Review Board (IRB) approved and will be performed in accordance with principles of research ethics set forth in the Belmont Report.
Informed consent: Signed informed consent will be obtained from the patients or their guardians.

Keywords: clinical trial; Parkinson′s disease; traumatic brain injury; cerebral vascular accident; stroke; multiple sclerosis; diabetic neuropathy; neurological disease; neurological damage


How to cite this article:
Weiss JN, Levy S. Neurologic Stem Cell Treatment Study (NEST) using bone marrow derived stem cells for the treatment of neurological disorders and injuries: study protocol for a nonrandomized efficacy trial. Clin Trials Degener Dis 2016;1:176-80

How to cite this URL:
Weiss JN, Levy S. Neurologic Stem Cell Treatment Study (NEST) using bone marrow derived stem cells for the treatment of neurological disorders and injuries: study protocol for a nonrandomized efficacy trial. Clin Trials Degener Dis [serial online] 2016 [cited 2018 Dec 14];1:176-80. Available from: http://www.clinicaltdd.com/text.asp?2016/1/4/176/196984


  Introduction Top


Currently, the approximately 600 known neurological diseases have no or limited medical interventions. In the course of treating optic neuropathies in the Stem Cell Ophthalmology Treatment Study (SCOTS), we incidentally have noted collateral improvements in neurological impairments in certain patients which we attribute to the intravenous application of autologous bone marrow derived stem cells (BMSCs). We have begun the neurologic BMSC treatment study to determine if specific intervention with autologous BMSCs can provide effective treatment for certain neurological diseases and injuries. The study is also abbreviated as the Neurologic Stem Cell Treatment study (NEST).

Intravenous administration of BMSCs is a well-established approach for the treatment of neurological disease and injury with much support from previous pre-clinical and clinical studies (Laroni et al., 2015). BMSCs and the associated bone marrow fraction are posited to improve neurological function through a number of different mechanisms (Teixeira et al., 2013). In regards their ability to penetrate the blood-brain barrier (BBB) following intravenous administration: within the diencephalon there are specific circumventricular organs that lie in the wall of the third ventricle and are characterized by their high permeability, fenestrated capillaries and absence of a normal BBB (Ganong, 2000). The BBB is a selectively permeable barrier of endothelial cells with tight junctions which form the capillaries of the brain. The lack of a BBB in the circumventricular organs facilitates their function of coordinating homeostatic mechanisms of the endocrine and nervous systems. The glial limitans is the barrier of astrocyte endfeet in association with the parenchymal basement membrane surrounding pericytes around capillaries and pial or arachnoid fibroblasts around the cerebral spinal fluid (CNS) (Alvarez et al., 2013). Absence of a normal BBB and glial limitans appears to allow for direct entry of the BMSCs and associated neurotrophic growth factors into the brain parenchyma, potentially impacting the neurons, glial tissue and neuronal transdifferentiation of BMSCs.

In addition to the use of intravenous BMSCs, the study will provide a treatment arm using the application of BMSCs to the intranasal tissue as a means of introducing BMSCs to the central nervous system (CNS). The trigeminal nerve provides sensory input from the nasal cavity and has been shown to provide a separate pathway into the pons and brain parenchyma for various substances provided intranasally. Placement of BMSCs in the inferior third of the nose surrounding the inferior meatus and concha allows access to the trigeminal nerve.

The purpose of the study is to evaluate the use of autologous BMSCs for the treatment of neurological diseases and damage. We hope to support their value in improving neurological function and activities of daily living for different neurological diseases or injury including, but not limited to cerebral vascular accident (CVA or stroke), traumatic brain injury (TBI); multiple sclerosis (MS), Parkinson's disease (PD), and diabetic neuropathy. The objective is to document that neurological deficits caused by various central and peripheral nervous system diseases and injuries that may be mitigated by the use of BMSCs.


  Methods/Design Top


Study design

NEST is a prospective, nonrandomized, open-label, efficacy clinical trial involving the isolation of autologous BMSCs and transfer to the vascular system or vascular and intranasal area in order to determine if such a treatment will provide a statistically significant improvement in neurological function for patients with certain neurological conditions. This will be performed in Margate, Florida in the United States. In this study, we will utilize neurotrophic factor-secreting BMSCs to treat neurological disorders or damage via transplantation of cells to the vascular system and cribriform plate.

Participant recruitment

A total of 300 patients will be admitted to the study. Recruitment will be achieved primarily through listing on the United States National Institutes of Health website for listing of clinical trials (www.clinicaltrials.gov).

Inclusion criteria

  • Have documented functional damage to the central or peripheral nervous system unlikely to improve with present standard of care;
  • Be at least 6 months post-onset of the disease;
  • If under current medical therapy (pharmacologic or surgical treatment) for the condition be considered stable on that treatment and unlikely to have reversal of the associated neurological functional damage as a result of the ongoing pharmacologic or surgical treatment;
  • Have the potential for improvement with BMSC treatment and be at minimal risk of any potential harm from the procedure;
  • Be over the age of 18 years and capable of providing informed consent;
  • Be medically stable and able to be medically cleared by their primary care physician for the procedure. Medical clearance means that in the estimation of the primary care practitioner, the patient can reasonably be expected to undergo the procedure without significant medical risk to health.


Exclusion criteria

  • All patients must be capable of an adequate neurological examination and evaluation to document the pathology, including the ability to cooperate with the exam;
  • Patients must be capable and willing to undergo follow-up neurological exams with the sub-investigators or their own neurologists as outlined in the protocol;
  • In the estimation of Dr. Weiss, the BMSC collection and treatment will not present a significant risk of harm to the patient's general health or to their neurological function;
  • Patients who are not medically stable or who may be at significant risk to their health undergoing the procedure;
  • Pregnancy at the time of treatment or becoming pregnant within 3 months of treatment;
  • No gender, racial/ethnic, or upper age restrictions.
  • Vulnerable populations.


Allocation and treatment arms

The two arms of the study will include:

Arm 1: Intravenous - approximately 16 mL of BMSC fraction filtered with a 150 μm filter and administered intravenously.

Arm 2: Intravenous combined with intranasal - approximately 13-14 mL of BMSC fraction filtered with a 150 μm filter administered intravenously with approximately 2-3 mL placed on the surface of the nasal mucosa of the inferior nasal meatus/concha.

Because this is an open-label, nonrandomized, efficacy study, there is no sham or placebo arm. Unless medically contraindicated or anticipated that there could be impairment of intranasal delivery, patients will be assigned to Arm 2.

Anesthesia

Anesthesia will be provided by the anesthesia physicians and staff at the Park Creek Surgery Center in accordance with good medical judgment and regulations of the surgery center and the State of Florida, USA. Typically the patients receive general anesthesia for the bone marrow aspiration. Risk of mortality from general anesthesia is estimated to be 8.2 per million hospital surgical discharges in USA during 1999-2005 (Li et al., 2009), 8.8 per 10,000 in the 24 hour peri-operative period from 1995 to 1997 (Arbous et al., 2001). In a large-scale meta-analysis by Bainbridge et al. (2012), 87 studies involving 21.4 million general anesthesia administrations showed a significant decline in associated deaths over the last 50 years; most recently risk of mortality was 34 per million in the 1990s-2000s. We believe there is sufficient evidence to support the safety of general anesthesia as will be provided in the NEST study.

BMSC collection and preparation

Based on medical judgment, approximately 180 mL of bone marrow aspirate will be collected from one or both of the patient's iliac bones in the pelvis in the operating room and that may involve one, two, or more separate sites. The bone marrow aspirate will not leave the operating room. For separation and collection of the mononuclear cell layer including the stem cells and additional components, an FDA Class II medical device will be used. The collected bone marrow aspirate will be placed in the device that will separate the components of the bone marrow and isolate the portion containing the adult stem cells, which will be done in a completely sterile, automated and self-contained fashion with minimal manipulation. Approximately 16 mL of mononuclear cell material containing the adult stem cells will be available for injection.

Post-procedure neurological exams

The follow-up neurological exams will be obtained the day after the procedure and then requested at 1, 3, 6, and 12 months following the procedure (post NEST) or at the recommended intervals of patient examination by neurologists. We will provide a follow-up schedule and will contact the patients postoperatively to remind them to comply with the follow-up examinations. Intent-to-treat (ITT) criteria will be used in the event of incomplete data collection. The study director and the principal investigator will be responsible for collecting required data and coordinating retention. Patients agree to allow Dr. Weiss and his associates to release any medical information to their neurologists and medical doctors. They also agree to provide access to their exams from their neurologist and medical doctor to Dr. Weiss and his associates. Scales for scoring patient outcomes may include:

  • Unified Parkinsons Disease Rating Scale (UPDRS) scale pre and post NEST treatment for Parkinson's disease;
  • Expanded Disability Status Scale (EDSS) pre and post NEST treatment for multiple sclerosis;
  • Neuropsychiatric evaluation pre and post NEST treatment for traumatic brain injury. Neuropsychiatric testing may include: numbers forward and backward, memory testing, word association testing, verbal learning testing, visual form discrimination.


Withdrawal of individual subjects

Patients can leave the NEST at any time for any reason if they wish to do so without consequences. Medical records within NEST will be available upon request to the patient or required agencies.

Sample size

A total of 300 patients were approved by our IRB. Sample size was based on the relatively high variance and natural attrition of the patient population.

Statistical analysis

Statistical analysis will be tailored to the number of diseases and variance of the treated populations. As the disease treated will be stable or progressing, improvements in patients can be attributed to the interventions. Differences will be detected and measured by chi-square or Fisher's exact test for categorical variables and Student's t-test for the continual variables.


  Initial Results Top


In the early stage of the NEST study, a patient suffering from Parkinson's disease for 6 years, receiving carbidopa, levodopa and entacapone administration was included. Following 1 month of NEST treatment, the patient reported: ability to smell, balance, muscle control, posture, smoothness of walking and speed of walking, voice level, and memory, are improving, facial muscles working better - losing mask appearance, less swallowing/aspiration and incontinence problems, lessening of disconnects during discussions, reduced fatigue issues and less depressed, and an improvement in sleep.


  Discussion Top


The treatment with BMSCs is a transfer of mesenchymal stem cells and the secreting growth factors to the tissues surrounding or within the nervous system for the purpose of improving function of that tissue. Bosi and Bartolozzi (2010) reviewed donation of hematopoietic stem cells and concluded it to be a safe procedure.

Diminished neurological function can occur as a result of progressive damage to the nervous system from disease or injury. The exact disease or injury process causing the damage may vary, but the end result may damage neurons in the central or peripheral nervous tissue and/or the glial cells which support the neurons and their function. Our treatment protocol relates to transferring cells from one part of the body (bone marrow) in a way that will maximize the damaged tissue's access to those cells in a safe and reasonable fashion. There are many diseases and injuries that cause progressive damage to these tissues, thus our goal is to treat the damaged tissue rather than a specific disease.

The safety of BMSC transplantation has been well established. Wakitani et al. (2011) followed up 41 patients following the use of BMSCs for joint treatment for up to 11 years and 5 months. They found no tumors or infections and concluded autologous BMSC transplantation to be a safe procedure. In a meta-analysis that BMSCs were used to treat acute myocardial infarction, Cong et al. (2015) found an overall significant improvement in left ventricular ejection fraction (LVEF) and other cardiac measurements at 3-6 months and 12 months following BMSC transplantation and concluded that intracoronary transplantation of BMSCs post ST-elevation myocardial infarction (STEMI) was safe and effective. In a recent meta-analysis including 23 randomized controlled studies regarding BMSC therapy for chronic ischemic heart disease (IHD) and congestive heart failure (CHF) in 255 patients, Fisher et al. (2014) found moderate evidence that BMSC transplantation improves LVEF even for a long time (greater than 1 year) in patients suffering from chronic IHD and CHF. In a study by Nishida et al. (2012) involving dogs with acute spinal cord injury (SCI), autologous BMSCs were cultured and injected into a spinal cord lesion. Results of 29-62-month follow-up showed no complications or worsening of neurological function. Thus, we believe that the safety of BMSC transplantation in NEST is well supported by the current evidence.

Cribriform plate administration may be provided by direct application of the BMSCs to the nasal mucosa or through intranasal inhalation. The complications of intranasally administered BMSCs are limited to potential local irritation, rhinorrhea, and to the side effects of inhaled liquids. We have identified no unique side effects of BMSCs provided intranasally in comparison to drugs or vehicles (Jiang et al., 2011). If directly placed intranasally, BMSCs will be placed in the lower 1/3 of the nasal mucosa in the inferior nasal concha and meatus. Chapman et al. (2013) reviewed intranasal administration of BMSCs in the treatment of central nervous system (CNS) dysfunction in humans. They identified both olfactory and trigeminal pathways of BMSC entry allowing both anterior and posterior regions of the brain exposure, as well as made a remark on the efficacy and noninvasiveness of intranasal delivery of BMSCs. Several studies of preclinical application of BMSCs and improvements in models of stroke, cerebral hypoxia, and Parkinson's disease were discussed (Bhasin et al., 2012; Lescaudron et al., 2012; Cox et al., 2016). Intranasal delivery has been shown to be clinically safe and effective. In a review of intranasal delivery of stem cells to the brain, Jiang et al. (2011) indicate that the approach overcomes the difficulties of other methods of delivery for the treatment of many neurological disorders. A number of recent preclinical studies utilizing BMSCs as well as other types of stem cells in various neurological diseases (stroke, ischemia, Alzheimers Disease, spinal cord lesions, intracerebral hemorrhage) demonstrated the therapeutic effect of stem cell delivery via the intranasal route (Ji et al., 2015; Mita et al., 2015; Ninomizy et al., 2015; Zhao et al., 2015). Danielyan et al. (2009) have elegantly demonstrated the direct intranasal delivery of mesenchymal stem cells to the murine brain; identifying migratory pathways that allow the cells to enter the brain and move to various portions of the brain and separately into the cerebral spinal fluid with movement across the cortex and into the brain parenchyma. We would like to demonstrate the safety and effectiveness of intranasal delivery of BMSCs in various neurological diseases and injuries, and provides the evidence that BMSCs have the ability to cross the blood-brain barrier successfully in a noninvasive fashion.

In summary, physicians and the healthcare industry typically require multiple studies and continuing efforts to explore the value of BMSC transplantation before widening clinical application. The goal of the NEST study is to demonstrate whether intravenous and intranasal administration of BMSC is safe and their combination may allow for improved responses.


  Trial Status Top


Recruitment is ongoing at the time of submission. [22]

 
  References Top

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Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61:1939-1958.  Back to cited text no. 1
    
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Bhasin A, Srivastava M, Bhatia R, Mohanty S, Kumaran S, Bose S (2012) Autologous intravenous mononuclear stem cell therapy in chronic ischemic stroke. J Stem Cells Regen Med 8:181-189.  Back to cited text no. 4
    
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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patient(s) will give his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
JNW and SL are responsible for overall study design and drafting and revision of the manuscript. JNW is responsible for clinical evaluation of patients and providing treatment. Both authors read and approved the final version of the manuscript before publication.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.



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