Regenerative medicine in the Middle East

Regenerative medicine in the Middle East

Dr Asawari Bapat (Aasa)

By Dr Asawari Bapat (Aasa)

M.B.B.S, D.P.B (CPS, Clinical Pathology), P.G.D.H.H.M (Hospital and Healthcare Management); Director of Quality and Regulatory Affairs, at Infohealth FZE, based in Dubai and US; Global Consultant for medical labs and cellular therapies for excellence in quality, regulatory compliance, accreditations and certifications; International Ambassador, aabb (American Association of Blood Banks) for cellular therapies in the Middle East; Advisor to the Parents Guide to Cord Blood foundation; Ex-chair for laying down Cord Blood banking regulations in India associated with DCGI, ICMR India.

In recent times we have seen an emergence of a new revolutionary medical field of regenerative medicine.[1] The ability to stimulate healing and restore function is a major advancement in medicine, which is normally focused on symptom management and long-term treatment. Current estimates indicate that approximately one in three individuals could benefit from regenerative medicine. It offers potential solutions and hope for people who have conditions today that are beyond repair.[2]

The term “regenerative medicine” was first found in a 1992 article on hospital administration by Leland Kaiser.[3] Kaiser’s paper closes with a series of short paragraphs on future technologies that will impact hospitals including one paragraph headed by ‘‘Regenerative Medicine’’ as a bold print title and stating, ‘‘A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.”[4]

Regenerative medicine involves the “process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function.”[5] Regenerative medicine holds the promise of engineering and healing damaged tissues and organs by using the body’s own repair mechanisms to functionally heal previously irreparable tissues or organs.[6] Xenotransplantation products i.e. organs or tissues between members of different species are also regulated in the cell therapy branch.

Vital to cellular and gene therapies is the promise of cells, particularly stem cells, to repair, replace, restore, regenerate cells, tissues and organs. Regeneration is a naturally occurring process done by stem cells, proteins and growth factors, extracellular matrices and scaffolds, small molecules to name a few. Regenerative medicine also includes the possibility of growing tissues and organs in the laboratory and safely implanting them when the body cannot heal by itself.[7] Due to this potential for regenerating and re-growing the cells, tissues and organs; it has opened many doors to providing better treatments and potential cure to many diseases using cellular therapies.

Cells derived from a patient’s own cells are referred to as “autologous” and when derived from a donor’s cells are referred to as allogeneic. If a regenerated organ could be derived from the patient’s own tissues or cells, this would potentially solve the problem of the shortage of organs available for donation, and the problem of organ transplant rejection.[8]

According to the US Food and Drug Administration (FDA); somatic cell therapy is defined as “any autologous, allogeneic, or xenogeneic cells that have been propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics ex vivo, to be administered to humans and applicable to the prevention, treatment, cure, diagnosis, or mitigation of disease or injuries.”[9] Cell therapy products include stem cells and stem cell derived products, such as those from blood-forming (hematopoietic), mesenchymal, embryonic, tissues and umbilical cord blood; cancer vaccines and immunotherapies, such as dendritic cell vaccines, activated T or B lymphocytes, monocytes, and modified or unmodified cancer cells.

Stem cells are a key component of regenerative medicine; they are the foundation for every organ and tissue in our body. There are different types of stem cells that come from various places in the body or are formed at different times in our lives. Stem cells have the inherent capability to develop through a process called differentiation into numerous distinct types of cells. Different types of stem cells include; embryonic stem cells, tissue-specific stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSC). Embryonic stem cells have been associated with ethical dilemmas and as a result not commonly used for cellular therapies. The primary assignment of stem cells is to replace cells from tissue that is lost or damaged in normal day-to-day living or in injury−cells in your skin, blood, and the lining of your gut. These stem cells can generate different cell types for specific tissue or organs in which they live. For example, blood-forming stem cells in the bone marrow and cord blood can give rise to red blood cells, white blood cells and platelets. However, blood-forming stem cells do not generate liver or lung or brain cells, and stem cells in other tissues and organs do not generate red or white blood cells or platelets. MSCs or “mesenchymal stem cells” refer to cells isolated from stroma, the connective tissue that surrounds tissues and organs.[10] MSCs are stem cells that have immunomodulatory properties and are being currently explored as treatments for numerous disorders. However, all MSCs are not the same. Their characteristic properties depend on the origin of the cells in the body and how they are isolated and grown.

Stem cell researchScientists are exploring different types of stem cells, including umbilical cord blood, cord tissue, placenta or perinatal cells, adipose or fat cells and bioengineered cells called induced pluripotent stem cells. Each cell has its unique qualities, with some being more versatile than others. Research is now underway to understand and develop various sources for stem cells, such as the MSCs adipose stem cells, Stromal Vascular Fraction, Wharton’s Jelly, amniotic cells, placental blood banking, etc.

A number of regenerative therapies under development begins with the patient’s own cells. For example, a patient’s own skin cells or autologous cells will be collected, reprogrammed or processed in a laboratory to give them particular characteristics, and then delivered back to the patient to treat his or her disease.[11] The importance of these types of regenerative therapies originates from the innate response of our bodies to heal, rejuvenate, regenerate and defend when injured or invaded by a disease. It stems from the possibilities to harness the natural resources of the body to heal itself probing deeper to find long-term solutions to understand the processes and required to help the body heal better, perhaps even cure us from deadly diseases.

Important steps of cellular therapies include protecting the existing cells, repairing damaged cells and tissues, promoting and regenerating cells, tissues and organs. Treatments include both in vivo and in vitro procedures. In vivo meaning studies and trials performed inside the living body to stimulate previously irreparable organs to heal themselves.  In vitro treatments are applied to the body through implantation of a therapy studied in the laboratory.[12]

Currently there are four major concentrations in the field of regenerative medicine.

Medical devices and artificial organs: For example, patients who are unable to control their bladder due to spinal cord injury or birth defects such as spina bifida learn how to manually empty their bladder but the complications include repeated infections, inability to urinate at will and regulate the buildup of urine creating life-threatening complications.

With the help of a new procedure pioneered at Wake Forest University in North Carolina patients like Kaitlyne McNamara and six other patients have new hope of treatment. Scientists were able to grow new bladders from patients’ own cells, which were then transplanted back to patients’ bodies. Dr Anthony Atala and his colleagues described the experiment as a long-term success for the seven patients treated, who ranged from toddlers to teenagers. This is the first ever laboratory-grown organ transplant placed into a human, all made possible by regenerative medicine to improve the quality of life for patients all over the world. Scientists world over are now working with this revolutionary technology to grow new body parts from patients’ own cells and tissues. With continued efforts, this technology will eliminate the risk of tissue rejection. It is trying to find out how medical devices can provide the ability to sustain patients during their long wait for a donor organ, and occasionally eliminate the need for a transplant altogether.

Tissue engineering and biomaterials hold the futuristic goal of regenerative medicine to maintain the body as it is, or as close to its natural state. This will eliminate the need to replace whole organs. Certain diseases are so destructive that patients require entirely new organs from willing donors. Heart disease affects many individuals and requires a heart transplant for healthy living. Although a patient may be able to survive long enough to receive a heart, the body may reject the foreign organ. Regenerative medicine has already successfully grown heart valves from human cells. With the use of biomaterials to create a mold, scientists engineer patients’ own cells to grow in the form of a heart valve. Biomarker and scaffolding were also utilized in the second successful transplantation of a synthetic tissue- engineered windpipe.[13] The windpipe was successfully grown after isolation of the patient’s own cells. Nanoparticles are particles between 1 and 100 nanometers (nm) in size with a surrounding interfacial layer. The interfacial layer is an integral part of nanoscale matter, fundamentally affecting all of its properties. Nanoparticles are being assessed for their use in bone regeneration, skin regeneration, bladder reconstruction, cell encapsulation, and cardiac function restoration.[14]

Cellular therapy is an area with many progressive treatments. A young child who is suffering from leukemia while receiving treatment to eliminate cancer cells loses healthy cells. Their tiny bodies have a critical need for stem cells that are transplanted from other sources, such as bone marrow or cord blood collected from a compatible donor. Most often, finding a compatible donor is a Herculean task. This critical need is solved by storing one’s own stem cells so, whenever needed, you could regenerate your system back to normal. The best example is the umbilical cord blood usually discarded at birth which contains stem cells. According to the Parents Guide to Cord Blood Foundation, a nonprofit organization helping parents and healthcare professionals by providing education and creating awareness; cord blood can be currently used to treat many hematological malignancies, genetic diseases and inherited metabolic disorders.

Clinical translation puts promising therapies into active clinical trials. Some conditions and diseases that currently under trial are heart diseases, stroke, cerebral palsy, autism, and diabetes.

Novel treatments and cellular therapies in the field of regenerative medicine are applicable to nearly every disease and disorder. They take interrelated approaches−rejuvenation, replacement and regeneration. Rejuvenation means amplifying the body’s natural ability to heal itself. Replacement involves using healthy cells, tissues or organs from a donor who is living or deceased to replace the damaged ones. Organ transplants, such as heart, kidney and liver transplants are good examples. The aim for transplants is to find ways to overcome the donor shortage, the need for immune-suppression and challenges with organ rejection. Regeneration considers the delivery of specific types of cells or cell products to the diseased tissues or organs, where they will ultimately restore the tissue and organ function. All this is done through cell-based therapy or by using cell products, such as growth factors.

In GCC (Gulf Cooperation Council) regenerative medicine is currently applied in the field of orthopedics, sports medicine, wound care, diabetes, plastic surgery, dermatology, cardiology, neurology, organ transplantation. There are currently 55 approved regenerative products available globally and each day the list is expanding. In the Middle East most of the regenerative products currently in use are for skin or wound repair, orthopedic or sports medicine cases. There are few products on the market for the treatment of cancer, cardiac disease, and diabetes that can be useful. Heart disease and cancer are among the leading causes of death locally, and diabetes is often difficult to treat and manage. By improving the quality of currently available products, patients in the Middle East can benefit tremendously.

If we look locally at cord blood banking, cord blood being a popular stem cell therapy, we find the Middle East highly lacking in number of transplants. Despite the high incidence of genetic diseases such as sickle cell and thalassaemia where cord blood has been proven to be an effective treatment modality, there is limited awareness amongst the locals, residents and care givers. For example, at present there are two public cord blood banks in Saudi Arabia−one public and one private cord blood bank in UAE, one public bank in Qatar. Despite many cord blood banking facilities operating in these regions that collect the samples and store in various locations globally such as in the UK and India, the awareness is quite low.

Over the last few years, some hospitals and clinics in the Middle East have shown varied interest in making cellular therapies and regenerative treatments available here locally. Emirates Specialty Hospital in Dubai opened the region’s first Regenerative Medicine Department in 2018. However, Saudi Arabia has taken the lead in GCC by starting many programs for regenerative medicine and for its number of stem cell transplants and cellular therapies performed. The recent use of CAR-T in treatment of cancer has huge potential in providing a better life for many cancer patients and is currently under exploration in GCC.

The most popular therapy in the Middle East is Platelet Rich Plasma or PRP and is categorized as a cellular therapy. PRP is an approved therapy in most of the GCC; primarily for uses in orthopedics, sports medicine, and cosmetics amongst some other branches. Unfortunately, many caregivers lack good techniques and basic training for aseptic processing jeopardizing patient’s health. Many doctors have limited training and start practicing on patients with limited competency which leads to complications and patient and customer dissatisfaction. The caregivers should be trained in cellular therapies and should possess skills to match the international standards. For example; the Interventional Orthopedic Foundation (IOF), the Orthobiologic Institute (TOBI) and Musculoskeletal (MSK) international are some of the benchmark organizations providing training, skill set to match international standards in the field of orthopedics and sports medicine.

The word of caution is to choose the international partners wisely. For example, the U.S. Stem Cell, Inc. has recently signed a new licensing agreement with High Rising Group to open and operate regenerative medicine clinics throughout the Middle East.[15] US Department of Justice has filed a suit against them and is currently facing action in US for negligence towards patients who lost their vision with autologous stem cell treatment in their clinics.

Regulations governing regenerative medicine and cellular therapies are primarily led by US FDA and European Agencies such as Human Tissue Authority, European Union Directives. The list of regulations in title 21 of the Code of Federal Regulations, called the CFR, all apply to the cell therapy products. The most relevant regulations are the tissue rules in part 1271, the biologics requirements outlined in the part 600 and 610, the investigational new drug requirements in part 312, and the drug manufacturing requirements in parts 211 and 212. Somatic cell therapies are regulated as biologics under the Public Health Service Act section 351, in contrast to human tissues, which are regulated under section 361, where the primary safety concern is infectious disease transmission.

Human cells are currently regulated as biologics if any of the following criteria are met: they are more than minimally manipulated, they are combined with another article other than a preservation or storage agent, they are used in a way that is not homologous to their normal function, or they have a systemic effect and are dependent upon the metabolic activity of living cells for their primary function. FDA also regulates clinical development under Investigational New Drug, or IND, and premarket approval will be required for human cells that meet any one of these criteria. For example, the adipose cells or fat cells widely used in cellular therapies in GCC are classified as a drug in the US due to the complexities involved in processing and requires strictest licensing. However, every country provides their own guidelines and regulations as seen in Japan, Korea, GCC and India. For example, in the UAE preliminary guidelines are provided from DHA (Dubai Health Authority), MOHAP (Ministry of Health and Prevention), DHCR (Dubai Healthcare Regulations) based on the applicable international guidelines.

An Accreditation Program is designed to grant an accreditation for specific activities, including a variety of cellular therapy activities, reflected on the accreditation certificate. Some of the accreditations specific to regenerative medicine and cellular therapies are US FDA, AABB, AATB, FACT and ISO. They review the complete menu of activities using a quality systems approach. For example: AABB Standards for Cellular Therapy Services covers all aspects of product collection, manufacturing, testing and patient care. Developed by a committee of experts, from a variety of organizations, including representatives from the FDA, the Standards for Cellular Therapy Services are designed to be broadly applicable to a range of activities, clinical programs, and cell types. Most accreditations have global reach in the application of quality management systems and technical requirements and accredit cellular therapy programs and facilities around the world. For example, AABB accreditation has helped facilities lead the way to a reputation of outstanding quality and the accreditations is a symbol of quality and safety and aimed to promote patient, donor, and product safety compatible with the universally accepted international standards.

Article reviewed by Christina Celluzzi, PhD, MS
Senior Manager, Cellular Therapies
AABB Center for Cellular Therapies

References

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[2]About Regenerative Medicine – Center for Regenerative Medicine ….” https://www.mayo.edu/research/centers-programs/center-regenerative-medicine/patient-care/about-regenerative-medicine.

[3] “Regenerative medicine: Historical roots and potential strategies in ….” https://www.sciencedirect.com/science/article/pii/S2213879X1500053X.

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[5] “Department of Regenerative Medicine & Translational Science ….” http://www.stmkolkata.org/rmts/why-rmts.html.

[6] “NIH Fact Sheets – Regenerative Medicine.” https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=62.

[7] “Regenerative Medicine in Organ and Tissue Transplantation: Shortly ….” 1 Aug. 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545302/.

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[9] “Application of Current Statuatory Authorities to Human Somatic … – FDA.” 14 Oct. 1993, https://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/UCM148113.pdf. Accessed 19 Sep. 2018.

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[11] “Stem Cell Basics I. | stemcells.nih.gov.” https://stemcells.nih.gov/info/basics/1.htm. Accessed 4 Sep. 2018.

[12] “RegenerativeMedicine.net – What is regenerative medicine?.” http://www.regenerativemedicine.net/What.html. Accessed 4 Sep. 2018.

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