Application of stem cell-based therapies will be the turning point in the treatment of hitherto inadequately treated or incurable diseases of the 21st century. But we urgently need stem cell regulations as a deterrent to indiscriminate use of stem cell products. An insight by Dr Chandra Viswanathan, Head, Regenerative Medicine, Reliance Life Sciences
Stem cells are special cells which are able to differentiate into either fewer cell types, called the multipotent adult stem cells or most cell types called the pluripotent embryonic stem cells, while self-renewing extensively to generate more stem cells. Human Embryonic stem cells (hESCs) are examples of pluripotent cells and adult stem cells like the Mesenchymal stem cells (MSCs) are multi-potent in nature. Because of their potency of differentiation, stem cells are often foreseen as the hope of novel cell replacement based therapies to regenerate tissues/ organs damaged by injury or disease. Transplantation of stem cells or their derivatives into respective tissues or organs, is considered as one of the most promising remedies for hitherto incurable diseases.
After almost a decade of experimentation, it has now become increasingly clear that realisation of this intuitively logical concept is far more complex than originally envisaged. Thus, the scope of regenerative medicine extends much beyond the simple paradigm of providing new building blocks to a failing organ, to processes that dynamically alters the molecular landscape within the tissue via a number of paracrine factors and other multiple potential reparative processes.
Even though the feasibility and safety of stem cell use has been reasonably established by several groups, the superior efficacy of stem cell therapy in clinical settings seems to be better only in certain clinical conditions so far. All current efforts are directed towards this.
Due to ethical issues involved regarding harvest of hES, the propensity for uncontrolled growth in vivo and the likely rejection upon differentiation, clinical focus shifted to the adult-derived phenotypes. The advent of bioengineered pluripotent stem cells from adult somatic tissues called the Induced Pluripotent cells, [iPSCs] has revolutionised the potential availability and applicability of personalised stem cells. The bioengineered platform has the potential to bypass the ethical and allogeneic limitation of hES and allows patient derived tissue to be reprogrammed back to the embryonic phenotype and the opportunity to utilise the ‘autologous’ approach. As newer sources of pluripotent cells provide the capacity to achieve specified tissue differentiation from all three germinal layers, newer enabling technologies will probably be a stepping stone to maximise repair potency and has now ignited renewed clinical interest. Genomic and proteomic evaluation of adult stem cells will throw more light on the small molecule development for the future, help in companion diagnostics, and make Theranostics very significant.
Such approaches would move naïve ‘first generation’ stem cells from achieving a specific limited therapeutic objective to another level of understanding delivery, evaluation of the risks and benefits of repeat therapy and use of well characterised, lineage specified stem cells, transplanted either alone or in combination, which will mark the beginning of ‘ second generation’ stem cell medicine.
So far, only haematopoietic stem cells based medical treatment is approved in the management of several acquired and congenital haematological disorders. As an extension to this, cord blood derived haematopoietic stem cells got recognised for its unique abilities. Several thousand cord blood transplants have been so far been conducted, and is now serving as an alternative to bone marrow transplants.
Reliance Life Sciences established the first public cord blood repository in this part of the world, and is licensed by the Drug Controller General of India (DCG (I)), India. In the last few years, we have supplied cord blood grafts to at least 75 patients, admitted to various institutes of the country. The other interesting stem cell type are the MSCs, initially isolated derived from the bone marrow, but now even from other sources like the umbilical cord tissue, umbilical cord blood, placental blood, adipose tissue, etc. MSCs are self-renewing, multi-potential, easy to cultivate, and immune modulatory in nature and hence are under extensive research to evaluate its potential in treating several hitherto unmet medical needs. These can differentiate into cells of mesodermal, ectodermal and endodermal origin. This along with their property to secreting soluble factors help induce an immune modulatory environment- making them an attractive option for cell based therapies. Reliance Life Sciences is actively researching the applicability of these cells in diabetes, cirrhosis, wound healing, neurological disorders, closely adhering to the National stem cell guidelines released by the ICMR in 2013, and ably supported by the Institutional Stem Cell Ethics Committee.
Reliance Life Sciences has been a pioneer in stem cell research with several ‘firsts’ to credit. It has a significant commitment to developing stem cell therapies, right from research, cell processing in cGMP facilities, clinical research and clinical practice. There is no other player in India comparable to Reliance Life Sciences in the stem cell therapy domain.
Limitations
Reliance Life Sciences has also completed clinical trials after regulatory approvals, using MSCs derived from the patient’s own bone marrow for myocardial infarction, Parkinson’s disease, spinal cord injury, application of stem cell-based therapies for stable vitiligo, non-healing diabetic ulcers, and autologous conjuctival and limbal stem cell graft. The strategy now is to see the effect of cell combinations at R&D and preclinical experiments. But novel and ‘not so routine’ approaches are less accepted by stem cell ethics committees and approving bodies.
The other limitation for stem cell research in India is the lack of sufficient funds for conduct of large clinical trials and access to appropriate preclinical disease models. The funding agencies need to step up their support further, in this area. We believe and as can be seen from scores of publications from global researchers, through stem cells, the potential to treat a wide range of disease conditions (viz. spinal injury, muscular dystrophy, Parkinson’s disease, multiple sclerosis, diabetes, retinitis pigmentosa, ALS etc.)
In India, there are multiple agencies which directly or indirectly govern stem cell research. i.e. Department of Biotechnology (DBT), Indian Council of Medical Research (ICMR) and the DCG (I). The revised comprehensive guidelines from the ICMR in India is aimed at guiding researchers and indirectly ensures ethical and responsible conduct of stem cell research. The efforts of the International Society for Stem Cell Research (ISSCR) stem cell standards committee in facilitating international guidelines and standards is a reflection of this global realisation.
The main concern in India now, is the absence of stem cell regulations, without which the translation is taking too long despite stem cell committees’ support with review of applications from industry and academia. This must come into force very soon, as it can be a deterrent to the mushrooming of stem cell clinics and indiscriminate use of stem cell products.
The way ahead
To keep the promise of cell-based therapies, we have miles and miles to tread. Although clinical trials of stem cell therapy have been criticised by a few as being premature, there is no substitute for the human model as stem cell therapies enter the era of translation. The pace of medical and scientific advance is gaining significant momentum, and the travel from the bench to the bedside takes time and patience and close collaboration among multiple disciplines alone will define success. With more and more new molecules under development, the present challenges faced by this industry feels the need for organ specific toxicity studies, which could be redressed using hES and adult stem cell-based toxicity experiments.
With the market size expected to touch the $200 million mark by the end of this decade, stem cell-based therapies will be a major component of the new era medicine. When results expected are significant, let us not dwell on the enormous cost implications. There are at least about 200 clinical trials in various stages registered in various websites, but results are yet to come!
Regenerative medicine, comprising stem cell therapies and tissue engineered products, is still at a nascent stage in India. It is expected to be definitely useful for those suffering from diabetes, cardiovascular disorders, neurological disorders, burns and wounds, osteoarthritis, osteoporosis, bone, cartilage (joints and replacements), liver disorders, congenital abnormalities and neoplasms.
Going by the results of the experiments from all corners of the globe, stem cell medicine and tissue engineered-based stem cell devices will find a major place in medical prescriptions in the next five to 10 years’ time frame. With a cohesive government initiative and appropriate funding, within the next 20 years, regenerative medicine will be the standard of care for replacing all tissue/ organ systems in the body, in addition to its extensive industrial use for pharmaceutical testing.
A conducive environment for international collaboration, industry academia relationships, safeguarding patents on process and products will instill the much needed confidence that researchers look forward to. In the coming months, we also hope to achieve major milestones starting with establishment of standards for the regulatory approvals and fast track review of applications within a defined time frame.
Just as discovery and usage of penicillin was the inflection point in the fight against infectious diseases, application of stem cell based therapies will be the turning point in the treatment of hitherto inadequately treated or incurable diseases of the 21st century.
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