Retinal and Optic Nerve Stem Cell Surgery [1st ed.] 9783030608491, 9783030608507

Table of contents :
Front Matter ....Pages i-ix
Stem Cells, PRP, Definitions, FDA (Jeffrey N. Weiss)....Pages 1-3
History of Retinal Stem Cell Surgery (Jeffrey N. Weiss)....Pages 5-6
Funding (Jeffrey N. Weiss)....Pages 7-11
ClinicalTrials.gov Listings (Jeffrey N. Weiss)....Pages 13-26
Study Protocols (Jeffrey N. Weiss)....Pages 27-34
Study Design/Method/Procedures (Jeffrey N. Weiss)....Pages 35-47
Informed Consent (Jeffrey N. Weiss)....Pages 49-63
Procedure: Additional Patient Explanation (Jeffrey N. Weiss)....Pages 65-68
Photos (Jeffrey N. Weiss)....Pages 69-79
Some Thoughts for the Future (Jeffrey N. Weiss)....Pages 81-83
Publications (Jeffrey N. Weiss)....Pages 85-86
Frequently Asked Questions (FAQ) (Jeffrey N. Weiss)....Pages 87-90

Citation preview

Retinal and Optic Nerve Stem Cell Surgery Jeffrey N. Weiss

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Retinal and Optic Nerve Stem Cell Surgery

Jeffrey N. Weiss

Retinal and Optic Nerve Stem Cell Surgery

Jeffrey N. Weiss Parkland, FL USA

ISBN 978-3-030-60849-1    ISBN 978-3-030-60850-7 (eBook) https://doi.org/10.1007/978-3-030-60850-7 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To the patients that have allowed me the privilege to serve.

Preface

Over the last 30 years, we have heard about stem cells and the possibility that they may treat presently untreatable and blinding retinal and optic nerve diseases. There have been animal studies, companies perform small studies and then disappear, but nothing concrete has materialized. The FDA has repeatedly changed their regulations precluding the stability businesses require for investing. Companies must develop a proprietary product or process that allows them to recoup their investment and earn a profit. What if a proprietary product is not necessary? What if the solution is simple? How could that be brought to the market? There is much misinformation in our journals that speak about this work but know nothing about it. I began working in the stem cell field in 2009. I performed retinal stem cell surgery on two American patients in Germany in 2010, seven American patients in Austria in 2011, and, finally, in the U.S.A in 2012. I have now performed the surgery on more than 500 patients in the U.S. In this book, I provide the basis and details, the protocols, informed consents, and other information that would be helpful to a physician or researcher interested in this work. I value your constructive opinions and comments. Parkland, FL, USA

Jeffrey N. Weiss

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Contents

1 Stem Cells, PRP, Definitions, FDA ����������������������������������������������������������   1 2 History of Retinal Stem Cell Surgery������������������������������������������������������   5 3 Funding ������������������������������������������������������������������������������������������������������   7 4 ClinicalTrials.gov Listings������������������������������������������������������������������������  13 5 Study Protocols������������������������������������������������������������������������������������������  27 6 Study Design/Method/Procedures������������������������������������������������������������  35 7 Informed Consent��������������������������������������������������������������������������������������  49 8 Procedure: Additional Patient Explanation��������������������������������������������  65 9 Photos����������������������������������������������������������������������������������������������������������  69 10 Some Thoughts for the Future������������������������������������������������������������������  81 11 Publications������������������������������������������������������������������������������������������������  85 12 Frequently Asked Questions (FAQ)����������������������������������������������������������  87

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Chapter 1

Stem Cells, PRP, Definitions, FDA

Stem cells are undifferentiated cells capable of self-renewal (reproduction) and are capable of producing specific types of cells, a process known as differentiation. Embryonic stem cells, extracted from blastocysts, may be stimulated to differentiate into specific cell types. In the developing embryo, these cells differentiate into ectoderm, endoderm, and mesoderm. Embryonic cells can differentiate into any type of cell, but this can be disadvantageous, as they can form tumors. Much of the early stem cell research was performed using this type of cell. Because of the source of their derivation, there has been much religious and moral controversy. Induced pluripotent stem cells are differentiated, or older cells, that can be stimulated to return to an undifferentiated state. This would create an inexhaustible supply of cells but mutations in the cell line may be a problem. Adult stem cells are found in cord blood, and different organs, including the bone marrow, and fat or adipose tissue. The term “adult” may be confusing because they are also found in fetal tissue. These cells are further developed than embryonic cells. The cell is considered adult, not the source. Adult stem cells, unlike embryonic stem cells, generally form cells in their own tissue type, making the chance of tumor formation unlikely. They also provide many types of growth factors that may stimulate the existing tissue to heal itself. The use of autologous stem cells precludes the necessity of immunosuppression when non-autologous cells are used. There is now extensive evidence that bone marrow derived stem cells (BMSC) can regenerate non-hematopoietic tissues, including neural cells. Unlike embryonic stem cells, the use of BMSC avoids ethical issues. BMSC have been successfully used for many years to treat leukemia with bone marrow transplants.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 J. N. Weiss, Retinal and Optic Nerve Stem Cell Surgery, https://doi.org/10.1007/978-3-030-60850-7_1

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Platelet-rich plasma (PRP) is the product of centrifuged whole blood with the red blood cells removed. It is an approximately 3–5 times physiologically concentrated source of growth factors, cytokines, and adult stem cells. The growth factors and cytokines include the following: • • • • • • • • •

Platelet-derived growth factor Transforming growth factor beta Fibroblast growth factor Insulin-like growth factor 1 and 2 Vascular endothelial growth factor Epidermal growth factor Interleukin 8 Keratinocyte growth factor Connective tissue growth factor

The platelets are activated by the thrombin and calcium chloride, which is used in preparation. Two PRP preparation methods have been approved by the US Food and Drug Administration (FDA). Anticoagulated whole blood undergoes a two-­ stage process of centrifugation in an FDA-approved, Class 2 device. This treatment discussed in this book involves human cells and tissue (bone marrow derived stem cells or BMSC) and is exempt from IND requirements 21CFR312.2(b) and not subject to FDA oversight because it satisfies the following requirements: (a) The material transferred is human cells, tissues, and cellular and tissue-based products (HCT/Ps) defined as “articles containing or consisting of human cells or tissues intended for implantation, transplantation, infusion or transfer into a human recipient” under 21 CFR 1261.3(d) (2011). (b) The patient involved remains in the operating room during the entire surgical procedure, and the bone marrow and separated cells will remain in the same operating room as the patient during the entire procedure. This would exempt the procedure from FDA oversight as the exception set forth in Section 1271.15(b) “removing HCT/P’s from an individual and implanting such HCT/ P’s into the same individual during the same surgical procedure.” (c) The HCT/Ps will undergo centrifugation only and therefore are considered minimally manipulated by FDA under 21 CRF 1271.10(a)(1). Specifically, “Minimal manipulation” is defined in 21 CFR 1271.3 (f) (2) as meaning “For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.” In the preamble to the final HCT/P registration rule, the FDA listed several techniques that could be undertaken without causing tissues to be more than minimally manipulated including tissues that are centrifuged, subjected to density gradient separation, subjected to selective removal of a specific type of cell, sterilized or frozen.

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In our protocols, the bone marrow aspirate is centrifuged in an FDA Class 2 device to provide separation of the stem cells satisfying the minimally manipulated criteria. There is no amplification or other interference with the function of the HCT/P.  There is no drug used in the separation process. Furthermore, the device used for this centrifugation has complied with the regulatory processes and met the requirements of a Class 2 device per FDA guidelines, including minimal manipulation. The material obtained is for homologous use only meeting the requirements of 21 CFR 1271.10(a) (2) which include the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with HCT/P.  The HCT/P is not being combined with a drug or device. Therefore, our technique is FDA compliant, and no “approval” is necessary. In 2016, President Obama signed the 21st Century Cures Act, which provided an FDA provision for a Regenerative Medicine Advanced Therapy Designation (RMAT). As described in Section 3033 of the 21st Century Cures Act, a drug is eligible for regenerative medicine advanced therapy (RMAT) designation if: (a) “The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations; (b) The drug is intended to treat, modify, reverse, or cure a serious or life-­threatening disease or condition; and (c) Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.” The Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics, section III.A., provides FDA’s interpretation of whether a disease or condition is serious or life-threatening and whether a drug is intended to treat a serious disease or condition. “The request for RMAT designation must be made either concurrently with submission of an Investigational New Drug application (IND) or as an amendment to an existing IND. We will not grant a RMAT designation if an IND is on hold or is placed on hold during the designation review. We generally do not expect you to submit primary data (data sets), but your request for regenerative advanced therapy designation should describe the preliminary clinical evidence. Please include a brief description of any available therapies for the disease or condition, the study design, the population studied, and the endpoint(s) used; and a description of the study results and statistical analyses (e.g., subgroup analyses).” Since our protocols are FDA compliant, and we are not using a drug, no IND is required; therefore, an RMAT designation is not applicable.

Chapter 2

History of Retinal Stem Cell Surgery

In 2009, I began my investigation of performing stem cell surgery for untreatable, potentially blinding, retina and optic nerve conditions. Following an extensive literature search, I located a clinic in Dusseldorf, Germany, that was performing retrobulbar injections of BMSC to treat age-related macular degeneration (AMD). I visited the center several times and I performed the first subretinal placement of BMSC on two American patients at the center in 2010. One of the patients came to my office in the United States and was interviewed by a local television station. She had regained the ability to read a large-print book (YouTube – retinal stem cell surgery). In 2011, I performed the stem cell surgery on seven American patients in Vienna, Austria. During this 2-year period, I was working on the stem cell surgery technique and mechanism, in consultation with ex-FDA attorneys, that would allow me to perform this procedure in the United States. I met with the FDA in 2011. I also visited/met with stem cell researchers from clinics in Mexico, Thailand, and Panama. The stem cell clinic in Tijuana, Mexico, was using intravitreal injections of adipose-­ derived stem cells (ADSC) to treat age-related macular degeneration (AMD) with anecdotal good results. However, I examined a patient that had undergone the ADSC in Mexico that had developed proliferative vitreoretinopathy with a total retinal detachment, after receiving a subsequent intravitreal injection of Avastin for AMD. The pathology report of the vitreous specimen demonstrated adipose tissue. I also heard of complications in patients who received ADSC for ophthalmic conditions at other centers. In 2016, three patients treated by a nurse in a Florida office with intravitreal ADSC lost their vision. The cases made national news and by innuendo, the supposed stem cell “experts” condemned all ocular stem cell procedures, because they were not “FDA approved.” A true “expert” would have been familiar with the discussion above and not defame the researchers who were following the rules to the letter by performing FDA compliant research.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 J. N. Weiss, Retinal and Optic Nerve Stem Cell Surgery, https://doi.org/10.1007/978-3-030-60850-7_2

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Of note, FDA regulations technically do not allow the use of ADSC for medical treatments outside of their approval. The FDA has ruled that the processing of the adipose tissue to isolate the stem cells is more than the “minimal manipulation” allowed by their regulations.

Chapter 3

Funding

Unless you are independently wealthy and a philanthropist, someone must pay you to work. At the end of the day, you can have all the good intentions and empathy in the world, but you must eat, wear clothes, have a place to live, and if you have a family, support them as well. Nothing can be accomplished in science, or in life, without money. Rent, equipment, supplies, personnel, etc., must all be paid for. A clinical trial, also called an interventional trial, is a type of research where participants receive a specific intervention that is dictated by a study protocol. The intervention may be a surgical procedure, drug, device, or a change to the participants’ behavior, such as a diet. Clinical trials may compare a new medical or surgical approach to no intervention. There are various sources that provide funding for clinical trials.

The National Institutes of Health (NIH) The NIH is the largest biomedical funding source in the United States. There has been a 20% inflation adjusted decline in the NIH budget over the last decade. Approximately 15–20% of grant submissions receive funding, and due to government budget sequestration, investigators receive only 90% of the approved funds. A 2007 US government study found that university faculty members spend approximately 40% of their research time navigating bureaucracy in order to receive funding for their work. A research grant is awarded to an individual at a university, but not to the same individual when he enters private practice, effectively removing an experienced researcher from government funding. NIH grants are typically for a 3-year period and end abruptly if not renewed. In addition, the researcher is unable to shift the funds to another project if the first project is not successful.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 J. N. Weiss, Retinal and Optic Nerve Stem Cell Surgery, https://doi.org/10.1007/978-3-030-60850-7_3

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Pharmaceutical Companies Pharmaceutical companies are commercial enterprises organized to make money. Approximately 75% of clinical trials in medicine are company sponsored. Such funding may introduce bias, as the study design or interpretation is more likely to favor the drug under consideration with the ultimate goal, the attainment of FDA approval. This is understandable as the time to develop a successful drug is 10–15 years, and the cost to achieve FDA approval has successively increased over the decades to approximately 1.2 billion dollars at the present time. An orphan disease is defined as any disease affecting up to 200,000 individuals in the United States. There are incentives offered to pharmaceutical companies through the Orphan Drug Act of 1983 to address the rare disease market. However, orphan diseases with larger numbers of patients or those diseases for which there may be less price resistance regarding any successful treatment may draw development efforts in an unfair way.

Nonprofit Organizations Like the NIH, nonprofit organizations use a panel of experts who decide the worthiness of a particular grant and determine the awarding of funding. As such, they suffer from the same problem as the NIH. Thomas Kuhn has pointed out that breakthrough insights frequently stem from the intersection of disciplines, not from within the discipline. Grant reviewers are generally within the same discipline and do not recognize the new paradigm that may have come from the work of scientists in other fields. They remain committed to the old paradigm that has shaped their beliefs, which prompted the physicist, Max Planck, to say, “New scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.” Also like the NIH, nonprofit organizations award grants to institutions, not to individual researchers in private practice.

Private-Funded Research This includes a broad pool of donors with a wide range of passions that may speed progress by investing in bold ideas, gambles, and risky projects. Decisions may be made quickly, not encumbered by large bureaucracies. A sense of urgency can be respected.

Patient-Funded Research

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Critics argue that gifts privatize research and steer resources toward areas of personal interest. Supporters argue that it is the personal choice of the funder whether money is spent on personal goods or personal research. Personally funded projects have a vested interest in solving the chosen problem and, unlike pharmaceutically funded research, are not subject to the profit motive or market forces.

Patient-Funded Foundations It is not uncommon for many patients with rare diseases or their families to set up support groups, particularly with the ready availability of social networking. In some cases, the only research foundations focused on particularly rare diseases have been initiated by patients and families affected by those diseases. There are over 7000 rare genetic diseases impacting 8–10% of the US population or about 25 million patients. When such a disease afflicts a high profile or financially successful individual, or their family member, that particular disease can receive disproportionate attention and support.

Patient-Funded Research In this model, the patient pays for participating in the clinical research. In terms of the research, this is similar to the private-funded model discussed above. Less common conditions and risky proposals may be studied, unencumbered by bureaucracy, and coupled with the ability to make quick decisions. Critics argue that desperate patients can be exploited and should not pay for clinical research. Clearly, people with resources decide how to use their resources. Not allowing patients to pay for research would restrict their ability to use their own resources as they see fit. Unlike other types of funding, patient-funded research is subject to market demands. If a study is too expensive, there will be less participants, unlike the situation where the funding is provided for the patient to participate in the research. The self-funding patient will be more inclined to demand information thus providing a more thought-out informed consent than in a study where free care is provided, as they want to receive their “money’s worth.” One can argue that free medical care may be considered an exploitative inducement to participate in research. Patient-funded studies are generally for conditions not being investigated by NIH, or pharmaceutical studies, and tend toward novel approaches for less prevalent medical problems. Patient-funded research has been criticized for, by its nature, it eliminates the participation of individuals who cannot afford to participate. One can make the

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same criticism for the other funding sources as unless the study pays the patient for participation, including travel costs, individuals may be unable to take the required time off from work, nor have the financial and personal support structure in place to engage in a study. Since the purpose of a research study is to determine whether the clinical intervention is of benefit, and such interventions may carry some medical risk, one could argue that aligning financial cost with participation creates a higher level of patient engagement, risk benefit assessment, and therefore informed consent. In addition, the ultimate benefits of basic and clinical research accrue to all individuals with a particular disease irrespective of financial wherewithal. Does profit taint the research? One could argue that all human activity creates bias; otherwise, there would be no activity. Unless the research is self-funded, researchers are always paid by some funding source; otherwise, they could not perform the research. Frequently, both NIH and pharmaceutical funding are proportional to the number of subjects the researcher enrolls in the study, which some may consider to be unethical. In this respect, the patient-funded study differs little from other types of studies. As pointed out previously, it is in the researcher’s interest to keep the patient cost at a reasonable level in order to encourage patient entry. The patient-funded study, which has a detailed protocol, has undergone Institutional Review Board review, is listed with ClinicalTrials.gov (NIH), is collecting data, and is publishing results, whether positive or negative, is an important form of research allowing the testing of ideas that would otherwise languish due to a lack of funding. All human endeavors require work and effort and therefore have financial costs. There is a range of how removed the patients are from those costs, depending on the research payment methodology. In the case of publicly funded clinical research, the patient may have low awareness of the cost of the clinical research as the funds are taken from the general tax base of whose allocation individuals have minimal awareness. In publicly funded research, the cost of an individual’s participation is spread out over millions of people, and therefore the percentage of cost that is the responsibility of an individual patient is low. This low awareness of source and percentage cost of participation removes these particular financial considerations from the informed consent process. On the other end of the spectrum, patient-funded research causes high awareness of the cost of that individual’s participation and causes a high percentage of the cost to be the responsibility of the participating patient. This high awareness enters the informed consent process as an additional consideration as patients weigh the potential personal benefit of participation. This causes a pause in this process, even for the wealthiest individuals. Pharmaceutical clinical research would fall in-between, with the actual costs being deferred to a later time, but still assumed by the individual patient needing the successfully proven care depending on the health insurance methodology.

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In considering the different methods of funding of clinical research, the overall benefit of properly done clinical research, from whichever funding source, should be kept in mind. All clinical research and patient care creates costs, which ultimately accrue to individuals in the society. It is only a matter of how directly those costs are felt by individuals. Unlike grants, with time-limited support, patient-funded studies may be self-perpetuating. As long as the public perceives benefit, the study may continue.

Chapter 4

ClinicalTrials.gov Listings

In the first three chapters, I have provided the scientific and regulatory basis for this work, the history, and the rationale for a patient-funded study. Decades after stem cells were discovered, the Stem Cell Ophthalmology Trial remains the only avenue for patients with “untreatable” retinal and optic nerve conditions. In the next sections, I will describe the mechanisms by which a clinical study may be performed. Provided is our listing on www.ClinicalTrials.gov, our protocols, study design, informed consent, and additional patient explanation. Photographs of the various postoperative stages of each surgical procedure are presented as are thoughts for the future. For those that are interested, there is a listing of our publications and answers to the most “frequently asked questions.” The Stem Cell Ophthalmology Treatment Study (SCOTS) is an Institutional Board Approved Study registered with NIH. ClinicalTrials.gov Identifier: NCT01920867. Here is the listing of SCOTS 1 on the NIH website. When SCOTS 1 fulfilled its enrollment (300 patients) the study ended, and SCOTS 2 began. The SCOTS 2 listing follows. Only pertinent information is provided.

SCOTS I • Stem Cell Ophthalmology Treatment Study (SCOTS) • ClinicalTrials.gov Identifier: NCT01920867

Purpose This study will evaluate the use of autologous bone marrow derived stem cells (BMSC) for the treatment of retinal and optic nerve damage or disease. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 J. N. Weiss, Retinal and Optic Nerve Stem Cell Surgery, https://doi.org/10.1007/978-3-030-60850-7_4

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Condition: • Retinal Disease Procedure: RB (Retrobulbar) • Procedure: ST (Subtenon) • Procedure: IV (Intravenous) • Procedure: IVIT (Intravitreal) • Procedure: IO (Intraocular) • Macular Degeneration • Hereditary Retinal Dystrophy • Optic Nerve Disease • Glaucoma Study Type: • Interventional Study Design: • Allocation: Non-Randomized • Endpoint Classification: Efficacy Study • Intervention Model: Parallel Assignment • Masking: Open Label • Primary Purpose: Treatment Official Title: • Bone Marrow Derived Stem Cell Ophthalmology Treatment Study Primary Outcome Measures: 1. Visual acuity [Time Frame: 1 day to 12 months] [Designated as safety issue: No] Best corrected visual acuity will be measured with Snellen Eye Chart and the ETDRS (Early Treatment Diabetic Retinopathy Study) Eye Chart when available at each post-procedure visit. Intervals at minimum will be first post-­ procedure day, then 3  months, 6  months, and 12  months post-procedure day. Recommended visit 1-month post-procedure day. Secondary Outcome Measures: 1. Visual fields [Time Frame: 1 day to 12 months] [Designated as safety issue: No] Visual fields will be evaluated with automated perimetry during post-procedure visits as needed and specifically at 6 months and 12 months. Estimated Enrollment: • 300 • Study Start Date: August 2013 Estimated Study Completion Date: • August 2017

Detailed Description

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Estimated Primary Completion Date: • August 2016 (Final data collection date for primary outcome measure) • • • •

Arms Assigned Interventions Active Comparator: RB, ST, IV Injections of BMSC retrobulbar (RB), subtenon (ST), and intravenous (IV)

• • • •

Procedure: RB (Retrobulbar) Retrobulbar injection of Bone Marrow Derived Stem Cells (BMSC) Other Name: Retrobulbar injection of stem cells

• • • •

Procedure: ST (Subtenon) Subtenon injection of Bone Marrow Derived Stem Cells (BMSC) Other Name: Subtenon injection of stem cells

• Procedure: IV (Intravenous) • Intravenous injection of Bone Marrow Derived Stem • Cells (BMSC) • • • • • •

Procedure: IVIT (Intravitreal) Intravitreal injection of Bone Marrow Derived Stem Cells (BMSC) Other Name: Intravitreal injection of stem cells Active Comparator: RB, ST, IV, IO Injection of BMSC retrobulbar, subtenon, intravenous, and intraocular (IO) with vitrectomy

• Procedure: IO (Intraocular) • Intraocular injection of Bone Marrow Derived Stem • Cells (BMSC) with vitrectomy prior to intraocular injection. For example, may include larger amount of stem cells in the intravitreal cavity, intraneuronal injections, or subretinal injections of stem cells • Other Name: Intraocular injection of stem cells with vitrectomy

Detailed Description Eyes with loss of vision from retinal or optic nerve conditions generally considered irreversible will be treated with a combination of injections of autologous bone marrow derived stem cells isolated from the bone marrow using standard medical and surgical practices.

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Retinal conditions may include degenerative, ischemic, or physical damage (examples may include macular degeneration, hereditary retinal dystrophies such as retinitis pigmentosa, Stargardt disease, non-perfusion retinopathies, post retinal detachment). Optic nerve conditions may include degenerative, ischemic, or physical damage (examples may include optic nerve damage from glaucoma, compression, ischemic optic neuropathy, optic atrophy). Injections may include retrobulbar, subtenon, intravitreal, intraocular, subretinal, and intravenous. Patients will be followed for 12 months with serial comprehensive eye examinations including relevant imaging and diagnostic ophthalmic testing.

Eligibility Ages Eligible for Study: • 18 Years and older (Adult, Senior) Genders Eligible for Study: • Both Accepts Healthy Volunteers: • No

Criteria • Inclusion Criteria: 1. Have objective, documented damage to the retina or optic nerve unlikely to improve. 2. Have objective, documented damage to the retina or optic nerve that is progressive. 3. Have less than or equal to 20/40 best corrected central visual acuity in one or both eyes and/or an abnormal visual field in one or both eyes. 4. Be at least 3 months post-surgical treatment intended to treat any ophthalmologic disease and stable. 5. If under current medical therapy (pharmacologic treatment) for a retinal or optic nerve disease be considered stable on that treatment and unlikely to have visual function improvement (e.g., glaucoma with intraocular pressure stable on topical medications but visual field damage). 6. Have the potential for improvement with BMSC treatment and be at minimal risk of any potential harm from the procedure. 7. Be over the age of 18. 8. Be medically stable and able to be medically cleared by their primary care physician or a licensed primary care practitioner for the procedure. Medical

Contacts and Locations

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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: 1. Patients who are not capable of an adequate ophthalmologic examination or evaluation to document the pathology. 2. Patients who are not capable or not willing to undergo follow-up eye exams with the Principal Investigator or their ophthalmologist or optometrist as outlined in the protocol. 3. Patients who are not capable of providing informed consent. 4. Patients who may be at significant risk to general health or to the eyes and visual function should they undergo the procedure.

Contacts and Locations Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. Please refer to this study by its ClinicalTrials.gov identifier: NCT01920867 Contacts • Contact: Steven Levy, MD • 203-423-9494 • [email protected] • Principal Investigator: Jeffrey Weiss, MD • Sub-Investigator: Steven Levy, MD • United Arab Emirates • Recruiting • Dubai, United Arab Emirates Responsible Party: • Retina Associates of South Florida ClinicalTrials.gov Identifier: • NCT01920867 History of Changes Other Study ID Numbers: • ICMS-2013-0019.

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Keywords Provided by Retina Associates of South Florida: • Stem Cells • Dry Macular Degeneration • Wet Macular Degeneration • Retinal Atrophy • Retinal Dystrophy • Hereditary Retinal Dystrophy • Retinitis Pigmentosa • Stargardt Disease • Cone Dystrophy • Cone-Rod Dystrophy • Maculopathy • Optic Nerve Disease • Optic Nerve Atrophy • Optic Atrophy • Ischemic Optic Neuropathy • Bone Marrow Derived Stem Cells • BMSC • BMC (Bone Marrow Cell) • Mesenchymal Stem Cells • MSC • Eye Disease • Eye Stem Cells • Ophthalmology • Ophthalmic Disease • Retina • Retinal Disease • Macular Degeneration • Age-Related Macular Degeneration • Myopic Macular Degeneration • Glaucoma • Ocular Hypertension • Eye Diseases • Retinal Degeneration • Cranial Nerve Diseases • Macular Degeneration • Retinal Diseases • Retinal Dystrophies • Nervous System Diseases Once we treated the 300 patients authorized in SCOTS 1, SCOTS 2, which allows the treatment of 500 patients, began. This is the current study.

Purpose

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Stem Cell Ophthalmology Treatment Study II (SCOTS2) This study is currently recruiting participants. • MD Stem Cells • ClinicalTrials.gov Identifier: NCT03011541

Purpose This study will evaluate the use of autologous bone marrow derived stem cells (BMSC) for the treatment of retinal and optic nerve damage or disease. • • • • • • • • • • • •

Condition Intervention Retinal Disease Age-Related Macular Degeneration Retinitis Pigmentosa Stargardt Disease Optic Neuropathy Nonarteritic Ischemic Optic Neuropathy Optic Atrophy Optic Nerve Disease Glaucoma Leber Hereditary Optic Neuropathy

• Procedure: Arm 1 • Procedure: Arm 2 • Procedure: Arm 3 Study Type: • Interventional Study Design: • Allocation: Non-Randomized • Intervention Model: Parallel Assignment • Masking: None (Open Label) • Primary Purpose: Treatment

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Official Title: • Bone Marrow Derived Stem Cell Ophthalmology Treatment Study II Primary Outcome Measures: • Visual Acuity [Time Frame: Change from pre-procedure to 12 months] Best corrected visual acuity will be measured with Snellen Eye Chart and the ETDRS (Early Treatment Diabetic Retinopathy Study) Eye Chart when available at each post-procedure visit. Intervals at minimum will be first post-procedure day, then 3  months, 6  months, and 12  months post-procedure day. Recommended visit 1-month post-procedure day. Secondary Outcome Measures: • Visual Fields [Time Frame: Change from pre-procedure to 12  months] Visual fields will be evaluated with automated perimetry during post-procedure visits as needed and specifically at 6 months and 12 months. Visual fields are a key measurement in patients with peripheral vision loss. • Optical Coherence Tomography (OCT) [Time Frame: Change from pre-­ procedure to 12 months] OCT thickness of the retinal nerve fiber layer the optic nerve and/or macula during the post-procedure visits as needed and specifically at 6 and 12 months – if available. Estimated Enrollment: • 500 Study Start Date: • January 2016 Estimated Study Completion Date: • January 2021 Estimated Primary Completion Date: • January 2020 (Final data collection date for primary outcome measure) • • • •

Arms Assigned Interventions Active Comparator: Arm 1 BMSC provided retrobulbar, subtenon, and intravenous for one or both eyes

• Procedure: Arm 1 • Procedure/Surgery: RB (Retrobulbar) • Retrobulbar injection of Bone Marrow Derived Stem Cells (BMSC) • • • •

Procedure/Surgery: ST (Subtenon) Subtenon injection of Bone Marrow Derived Stem Cells (BMSC) Procedure/Surgery: IV (Intravenous) Intravenous injection of Bone Marrow Derived Stem Cells (BMSC)

Purpose

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Other Names: • Retrobulbar (RB) • Subtenon (ST) • Intravenous (IV) • Active Comparator: Arm 2 • BMSC provided retrobulbar, subtenon, intravitreal, and intravenous for one or both eyes. • Procedure: Arm 2 • Procedure/Surgery: RB (Retrobulbar) • Retrobulbar injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: ST (Subtenon) • Subtenon injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: IV (Intravenous) • Intravenous injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: IVIT (Intravitreal) • Intravitreal injection of Bone Marrow Derived Stem Cells (BMSC) • Active Comparator: Arm 3 • BMSC provided either intra-optic nerve or subretinal for eye with worse vision with fellow eye receiving either retrobulbar and subtenon or retrobulbar, subtenon, and intravitreal; followed by intravenous. • Procedure: Arm 1 • Procedure/Surgery: RB (Retrobulbar) • Retrobulbar injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: ST (Subtenon) • Subtenon injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: IV (Intravenous) • Intravenous injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure: Arm 2 • Procedure/Surgery: RB (Retrobulbar) • Retrobulbar injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: ST (Subtenon) • Subtenon injection of Bone Marrow Derived Stem Cells (BMSC)

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4  ClinicalTrials.gov Listings

• Procedure/Surgery: IV (Intravenous) • Intravenous injection of Bone Marrow Derived Stem Cells (BMSC) • Procedure/Surgery: IVIT (Intravitreal) • Intravitreal injection of Bone Marrow Derived Stem Cells (BMSC) • • • • •

Procedure: Arm 3 Procedure/Surgery: RB (Retrobulbar) Retrobulbar injection of Bone Marrow Derived Stem Cells (BMSC) Procedure/Surgery: ST (Subtenon) Subtenon injection of Bone Marrow Derived Stem Cells (BMSC)

• • • •

Procedure/Surgery: IV (Intravenous) Intravenous injection of Bone Marrow Derived Stem Cells (BMSC) Procedure/Surgery: IO (Intraocular) Intraocular injection of Bone Marrow Derived Stem Cells (BMSC) with vitrectomy prior to intraocular injection. For example, may include larger amount of stem cells in the intravitreal cavity, intraneuronal injections or subretinal injections of stem cells.

Detailed Description Eyes with loss of vision from retinal or optic nerve conditions generally considered irreversible will be treated with a combination of injections of autologous bone marrow derived stem cells isolated from the bone marrow using standard medical and surgical practices. Retinal conditions may include degenerative, ischemic, or physical damage (examples may include macular degeneration, hereditary retinal dystrophies such as retinitis pigmentosa, Stargardt disease, non-perfusion retinopathies, post retinal detachment). Optic nerve conditions may include degenerative, ischemic, or physical damage (examples may include optic nerve damage from glaucoma, compression, ischemic optic neuropathy, optic atrophy). Injections may include retrobulbar, subtenon, intravitreal, intraocular, subretinal, and intravenous. Patients will be followed for 12 months with serial comprehensive eye examinations including relevant imaging and diagnostic ophthalmic testing.

Eligibility Ages Eligible for Study: • 18 Years and older (Adult, Senior)

Criteria

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Sexes Eligible for Study: • All Accepts Healthy Volunteers: • No

Criteria Inclusion Criteria: • Have objective, documented damage to the retina or optic nerve unlikely to improve. • Have objective, documented damage to the retina or optic nerve that is progressive and have less than or equal to 20/40 best corrected central visual acuity in one or both eyes and/or an abnormal visual field in one or both eyes. • Be at least 3 months post-surgical treatment intended to treat any ophthalmologic disease and is stable. • If under current medical therapy (pharmacologic treatment) for a retinal or optic nerve disease be considered stable on that treatment and unlikely to have visual function improvement (e.g., glaucoma with intraocular pressure stable on topical medications but visual field damage). • 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. • Be medically stable and able to be medically cleared by their primary care physician or a licensed primary care practitioner 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: • Patients who are not capable of an adequate ophthalmologic examination or evaluation to document the pathology. • Patients who are not capable or not willing to undergo follow-up eye exams with the Principal Investigator or their ophthalmologist or optometrist as outlined in the protocol. • Patients who are not capable of providing informed consent. • Patients who may be at significant risk to general health or to the eyes and visual function should they undergo the procedure.

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Contacts and Locations Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. Please refer to this study by its ClinicalTrials.gov identifier: NCT03011541 Contacts • Contact: Steven Levy, MD • 203-423-9494 • [email protected] Locations • United States, Florida • The Healing Institute • Recruiting • Margate, Florida, United States, 33063 • Contact: Steven Levy, MD 203-423-9494 [email protected] • Principal Investigator: Jeffrey N Weiss, MD • United Arab Emirates • Enrolling by invitation • Dubai, United Arab Emirates • Sponsors and Collaborators • MD Stem Cells • Investigators • Study Director: • Steven Levy, MD • MD Stem Cells • Principal Investigator: • Jeffrey N. Weiss, MD • The Healing Institute

More Information Additional Information: • Seeing is Believing: South Florida Doctor Helps the Blind See Through Experimental Procedure • Baltimore woman once blind, regains vision after retinal stem cell surgery (see link, website, clinicaltrials.gov).

More Information

Responsible Party: • MD Stem Cells • ClinicalTrials.gov Identifier: • NCT03011541 History of Changes Other Study ID Numbers: • SCOTS2 Study First Received: • January 1, 2017 Last Updated: • July 17, 2017 Keywords Provided by MD Stem Cells: • Stem Cells • Bone Marrow Derived Stem Cells • BMSC • Mesenchymal Stem Cells • MSC • Eye Disease • Ophthalmology • Ophthalmic Disease • Retina • Retinal Disease • Macular Degeneration • Age-Related Macular Degeneration • Myopic Macular Degeneration • Geographic Atrophy • Dry Macular Degeneration • Wet Macular Degeneration • Retinal Atrophy • Retinal Dystrophy • Hereditary Retinal Dystrophy • Malattia Leventinese • Retinitis Pigmentosa • Stargardt Disease • Cone Dystrophy • Rod-Cone Dystrophy • Cone-Rod Dystrophy • Maculopathy • Optic Nerve Disease • Optic Atrophy

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• • • • • • • • • • • • • • • • • • • • • • • • • • • • •

4  ClinicalTrials.gov Listings

Optic Neuropathy Ischemic Optic Neuropathy Additional relevant MeSH terms: Peripheral Nervous System Diseases Macular Degeneration Atrophy Retinitis Retinitis Pigmentosa Optic Nerve Diseases Retinal Diseases Optic Neuropathy, Ischemic Optic Atrophy, Hereditary, Leber Nervous System Diseases Optic Atrophy Neuromuscular Diseases Retinal Degeneration Eye Diseases Pathological Conditions, Anatomical Eye Diseases, Hereditary Retinal Dystrophies Genetic Diseases, Inborn Cranial Nerve Diseases Vascular Diseases Cardiovascular Diseases Optic Atrophies, Hereditary Heredodegenerative Disorders, Nervous System Neurodegenerative Diseases Mitochondrial Diseases Metabolic Diseases

Institutional Review Board approval in the United States is limited to those patient 18 years of age and older. We are able to treat patients younger than 18 years of age at Fakeeh University Hospital, in Dubai. This is a modern, state-of-the art hospital with excellent support services. The hospital is approved by the US Joint Commission on Accreditation.

Chapter 5

Study Protocols

• Study Protocols (submitted to the IRB). I have included the most recent, SCOTS 2 protocol. • Protocol Title: • Bone Marrow Derived Stem Cell Ophthalmology Treatment Study II • Protocol Number: 2 • Date of Protocol: October 23, 2015 • • • • • • •

Working Title: SCOTS II Sponsor and Principal Investigator: Jeffrey N. Weiss, MD Retina Associates of South Florida 5800 Colonial Drive, Suite 300 Margate, FL 33063 Telephone 954-975-0044

• • • • • •

Sub-Investigator: Steven Levy MD MD Stem Cells 412 Main Street, Suite I Ridgefield, CT 06877 Telephone 203-423-9494

• • • • •

Primary Site: Retina Associates of South Florida 5800 Colonial Drive, Suite 300 Margate, FL 33063 Telephone 954-975-0044

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 J. N. Weiss, Retinal and Optic Nerve Stem Cell Surgery, https://doi.org/10.1007/978-3-030-60850-7_5

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5  Study Protocols

Supplemental Site: Park Creek Surgery Center 6806 North State Road 7 Coconut Creek, Florida 33073

Introduction Type of Research This is a human clinical study involving the isolation of autologous bone marrow derived stem cells (BMSC) and its transfer to the eyes via retrobulbar, subtenon, intraocular, and intravenous in order to determine if such a treatment will provide a statistically significant improvement in visual function for patients with retinal and optic nerve eye disease or damage. BMSC are predominately CD34 and are considered by investigators to be pluripotent. In this study, we will be providing a transfer of these pluripotent stem cells from the bone marrow where they predominately reside to damaged retinal and optic nerve tissue. This research is not federally funded nor subject to federal oversight. There is no HDE involved. This treatment involves human cells and tissue (bone marrow derived stem cells or BMSC) and is exempt from IND requirement 21CFR312.2(b) and not subject to FDA oversight because it satisfies the following requirements: 1. The material transferred is human cells, tissues, and cellular and tissue based products (HCT/Ps) defined as “articles containing or consisting of human cells or tissues intended for implantation, transplantation, infusion or transfer into a human recipient” under 21 CFR 1261.3(d) (2011). 2. The patient remains in the operating room during the entire surgical procedure, and the bone marrow and separated cells will remain in the same operating room as the patient during the entire procedure. This would exempt the procedure from FDA oversight as the exception set forth in Section 1271.15(b) “removing HCT/ P’s from an individual and implanting such HCT/P’s into the same individual during the same surgical procedure.” 3. The HCT/Ps will undergo centrifugation only and therefore are considered minimally manipulated by FDA under 21 CRF 1271.10(a)(1). Specifically, “Minimal manipulation” is defined in 21 CFR 1271.3 (f) (2) as meaning “For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.” In the preamble to the final HCT/P registration rule, FDA listed several techniques that could be undertaken without causing tissues to be more than minimally manipulated including tissues that are centrifuged, subjected to density gradient separation, subjected to selective removal of a specific type of cell, sterilized or frozen.

Introduction

29

In our protocol, the bone marrow tissue will be centrifuged in an FDA Class 2 device to provide separation of the stem cells satisfying the minimally manipulated criteria. There will be no amplification or other interference with the function of the HCT/P. There is no drug used in the separation process. Furthermore, the device used for this centrifugation has complied with the regulatory processes and met the requirements of a Class 2 device per FDA guidelines, including minimal manipulation. 4. The material obtained is for homologous use only meeting the requirements of 21 CFR 1271.10(a) (2) which includes the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with HCT/P.  We believe that bone marrow derived stem cells function in the same fashion no matter their location. 5. The HCT/P is not being combined with a drug or device.

Purpose and Objective of the Study The purpose of the study is to continue to evaluate the use of autologous bone marrow derived stem cells for retinal and optic nerve tissue damage and determine whether they will show a statistically significant improvement in visual function for progressive and otherwise untreatable retinal and optic nerve eye disease or damage. The objective is to determine which diseases or injuries of the retina and optic nerve and at what stages they may be most effectively treated.

Background of the Study Rationale for SCOTS II The original Bone Marrow Derived Stem Cell Ophthalmology Study or SCOTS is being successfully conducted but will reach the limit of its enrollment soon. This study has been very successful in establishing the safety and efficacy of bone marrow derived stem cells (BMSC) in a number of retinal and optic nerve diseases. The study has begun publishing and will continue to publish based on the data from patients who have undergone treatment. However, there has been variability in demographics of the patients including age, length of disease process, visual acuity, comorbidities, and the fact that many of the patients have had a mixture of retinal and/or optic nerve diseases. In addition, the need to continue establishing the value of BMSC treatment for the medical community remains. Medicine is traditionally very slow to adopt new procedures and approaches to treatment. Physicians and the healthcare industry

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5  Study Protocols

typically require multiple studies and continuing effort to explore and establish procedures. Therefore, it remains our goal to continue treating patients within an IRB approved protocol, which will allow publishing of results in reputable medical journals. SCOTS II will allow us to continue recruiting patients and to increase the numbers of more closely matched demographics within specific diseases. Current Publications (See Chap. 11) Background Information Regarding Original SCOTS (ICMS-2013-0019) The clinical use of stem cells has been ongoing for several years now in many parts of the world. It is estimated that over 20,000 patients have undergone stem cell therapies of one type or another with variable improvements in their disease conditions. Sources for these stem cells have included umbilical cord, fetal, adipose, placental, and bone marrow. Depending on the country and regulatory environment, there has been variation in the scientific reliability of these treatments. However, the continued anecdotal reports of subjective improvements in many conditions and testimonials on the part of individuals with progressive or untreatable diseases provide encouragement for patients to seek out these treatments. The use of bone marrow derived material in orthopedics for enhancement of healing, joint treatment, and other orthopedic procedures is well established in the United States. Bone marrow derived stem cells have also been used in patients with a variety of diseases including neurologic, cardiac, immunologic, degenerative, and ophthalmic. Clinics in Germany, Austria, Thailand, Mexico, China, and other countries have treated patients with various eye diseases with stem cells and anecdotal results have been encouraging. The continuing complaint within the medical community in the United States is a lack of objective, scientifically verified results. Therefore, ophthalmologic stem cell treatments in the United States remain marginalized, and patients and their physicians remain confused as to its value. The time has come to provide a solid study of the effects of BMSC on damaged retinal and optic nerve tissue and the variety of progressive eye disease responsible for that damage. This will help establish which diseases are most likely to benefit and at what stages they are likely to benefit in order to provide guidelines for treatment.

Introduction

31

Participant Selection A. Inclusion and Exclusion Criteria –– Inclusions: The treatment with BMSC is a tissue transfer of active, predominately CD34 stem cells from the bone marrow to the tissues surrounding or within the eye for the purpose of improving function of that tissue. Diminished visual acuity (central vision or what the patient can read on the eye chart) and reduced peripheral vision (vision to the side) can occur as a result of progressive damage to the retina or optic nerve from disease or injury. The exact disease or injury process causing the damage may vary, but the end result may be damage to photoreceptors of the retina; to the support cells of the photoreceptors called the RPE/retinal pigment epithelium; to the inner or outer plexiform layer of retinal neurons; to the nerve fiber layer forming the optic nerve either within the retina to the ganglion cell bodies/axons or of the ganglion cell axons or glial support cells within the optic nerve proper; or to the vascular supply of any of these tissues. It is important to understand that 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. Our goal is treatment of the damaged tissue rather than a specific disease. To be eligible for treatment patients must: 1. Have objective, documented damage to the retina or optic nerve unlikely to improve. 2. Have objective, documented damage to the retina or optic nerve that is progressive 3. Have less than or equal to 20/40 central visual acuity in one or both eyes and/or an abnormal visual field in one or both eyes. 4. Be at least 3 months post-surgical treatment intended to treat any ophthalmologic disease and is stable. 5. If under current medical therapy (pharmacologic treatment) for a retinal or optic nerve disease be considered stable on that treatment and unlikely to have visual function improvement (e.g., glaucoma with intraocular pressure stable on topical medications but visual field damage).

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6. Have the potential for improvement with BMSC treatment and be at minimal risk of any potential harm from the procedure. 7. Have no alternative treatment that could improve their visual function at the stage of disease presenting. 8. Be over the age of 18. 9. Be medically stable and able to be medically cleared by their primary care physician or a licensed primary care practitioner 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. –– Restrictions: 1. All patients must be capable of an adequate retinal examination and evaluation to document the pathology. This will include the ability to cooperate with the exam, sufficiently clear media (cornea, lens, vitreous), and sufficient pupillary dilation. 2. Patients must be capable and willing to undergo follow-up eye examinations with Dr. Weiss or their ophthalmologist or optometrist as outlined in the protocol. 3. Patients must be capable of providing informed consent. 4. In the estimation of Dr. Weiss, the BMSC collection and eye treatment will not present a significant risk of harm to the patient’s general health or to the eyes and visual function. 5. Patients with retinal or optic nerve damage actively undergoing treatment providing the potential for improvement in visual function will not be eligible. At least 3 months must have elapsed following any treatment for non-­posterior disease (e.g., cataract surgery) or posterior segment disease (e.g., laser photocoagulation or intravitreal injection of VEGF inhibitors for wet macular degeneration) before the patient may be eligible. 6. Patients who are not medically stable or who may be at significant risk to their health undergoing the procedure will not be eligible. 7. Women of childbearing age must not be pregnant at the time of treatment and should refrain from becoming pregnant for 3 months post treatment. B. Gender – no restrictions. Women of child bearing age are eligible, but must not be pregnant at the time of treatment. C. Racial/ethnic origin – no restrictions. D. Vulnerable populations – no vulnerable populations will be eligible. E. Age – no patients under the age of 18 are to be enrolled. For those 18 years and older, there are no age restrictions. F. Total number of participants to be enrolled: 500.

Suggested Reading

33

• Explanation of participant number chosen: • Many retinal and optic nerve diseases, although varying in etiology, have similar detrimental effects on the photoreceptors, retinal pigment epithelium, or neural tissue. The sample size or number of participants proposed is based on the following: 1 . The size of the effect the trial should detect. 2. The Alpha or probability of Type I error (error of reporting the treatment is effective but in reality, it is not). 3. Power or the probability of avoiding Type II error (Beta or the error of reporting the treatment is ineffective but in reality, it is effective). 4. The potential loss of data from inadequate follow-up on the part of the patients over the 5 requested patient exams (1 day, 1 month, 3 months, 6 months, and 12 months). 5. Alpha is set to generally accepted statistical significance for clinical trials, which is p