Dr Indumathi Mariappan completed her doctoral training in the area of Cell Biology and Molecular Biology at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad in 2005. She also underwent a three-year post-doctoral training at CCMB before joining the Stem Cell Biology Laboratory at LVPEI in 2008. Dr Mariappan’s lab is involved in basic and translational research towards addressing the problems of retinal and corneal diseases using different sources of adult and pluripotent stem cells. Her group is currently exploring the basic biology of limbal stem cells and the applications of embryonic stem cells (hESCs) and patient-specific induced pluripotent stem cells (hiPSCs) in disease modelling and regenerative medicine. In an email interview with India Medical Times, She speaks about the mini human eyes that her team developed using stem cells.
Dr Indumathi Mariappan, please introduce yourself for our readers.
I am a basic research scientist, with a PhD and post-doctoral training from the Centre for Cellular and Molecular Biology (CCMB), Hyderabad and worked in the areas of cell biology and molecular biology for about 8 years before joining the stem cell research team at the L V Prasad Eye Institute, Hyderabad. Since 2008, my research group at LVPEI has been involved in basic and translational research towards addressing the problems of retinal and corneal diseases, using different sources of adult and pluripotent stem cells. We are currently exploring the possibility of using stem cell derived ocular cells and engineered tissues for regenerative applications.
Is it true that your lab has made progress in developing human eyes from stem cells?
Yes, our team was successful to generate miniature eye-like structures from stem cells. These specialized stem cells are capable of making different cells of the body and are therefore called pluripotent. Such master stem cells can be derived from fertilized embryos. But this may have some ethical concerns. Other alternative is to convert any cells of the body, say a skin or blood cells to become pluripotent. A Japanese group led by Prof Shinya Yamanaka at the Kyoto University pioneered this approach in 2007 and showed that it is possible to make pluripotent stem cells by introducing four important stem cell genes into skin cells. This technique has revolutionized the area of stem cell research and received the Nobel Prize in Physiology or Medicine in the year 2012. These stem cells are called induced pluripotent stem cells (iPSCs) and are capable of making any cells of the body. This has brought a newer hope for regenerating various tissues, such as the retina that are not known to carry any stem cells for regeneration.
Our lab has adopted this technique to make iPSCs from the skin and these stem cells when grown under specialized conditions can generate different parts of the eye, including the retina in a dish. These miniature tissues grown in cell culture dishes are called organoids and are normally in the size range of 2-4 mm. So far, many scientists from across the globe have shown that stem cells can be programmed to make organoids of the brain, liver, pancreas, lungs, kidney, heart, skin, retina etc. In spite of their smaller size, they are complex structures both in terms of the tissue morphology, cellular arrangement and organization. They may not become direct substitutes to adult sized organs, but are wonderful sources to harvest tissue-specific cells that may have larger applications in disease modelling, drug testing and in cell-based therapies. Along this line, our team has worked out methods to make eye tissues such as corneal and retinal organoids from skin cell derived iPSCs.
What is the future of your research?
We are currently testing if the corneal and retinal cells taken from such miniature organoids can be used for the treatment of different disease conditions of the eye. We are now experimenting with animal models to understand the safety of these stem cell-derived eye cells, their usefulness in vision restoration and to figure out the best delivery methods to be adopted for future clinical applications.
Can this be a huge breakthrough in the field of eye transplantation?
The disease conditions that we are first aiming to find a treatment option using this newer approach of cell therapy are the retinal dystrophies. Retina is at the backside of the eye and it functions as an image-forming screen. It contains specialized cells that perceive the light and send the signals to the brain and enable us to see what we see. In some patients suffering from retinal problems, these cells are either unable to function normally or die gradually over time. This results in gradual loss of vision, night blindness or colour blindness and can finally lead to total vision loss. This can happen early during childhood as in the case of genetic conditions such as the congenital retinal dystrophies or can happen in older patients as they age, as in age-related macular degenerations. Right now we don’t have a definitive treatment option to restore vision in such patients. All efforts are taken mainly to delay disease progression and also to provide rehabilitation support to help these patients become more self-reliant, both socially and professionally. Here, we are aiming to develop a cell-based therapy with the hope that the transplanted retinal cells may help the patients to regain their lost vision or at least help them to retain their vision for a longer time. So, we are not aiming for whole eye transplantation. Instead, we are experimenting to restore the function of defective retinas using cell therapy.
How can we use it for traumatic conditions of the eyes?
Trauma can affect any parts of the eye. Cell therapies are already offered to a subset of patients suffering from corneal surface burns, acid/alkali injuries etc. Here, the adult corneal stem cells from the patient’s unaffected eye are used to treat the affected parts of the cornea. These stem cells reside at the corneal periphery and a small 2 mm biopsy of the healthy tissue from this region is sufficient to treat the entire corneal surface of the affected eye. This therapy was developed by our team of cornea experts comprising of Dr Virender S Sangwan, Dr Sayan Basu and stem cell scientists in 2004 and more than 1000 patients have directly benefitted so far. The long-term clinical success and vision restoration rate is approximately 70% over the years. This work has been extensively published in peer-reviewed journals, meetings and media reports and successfully adopted by clinicians across the globe. However, if both eyes are affected and the patient’s own corneal stem cells are not available, then it is feasible that their skin derived iPSCs can be used to make corneal organoids to harvest corneal stem cells for tissue regeneration. However, this needs thorough evaluation in laboratory models and in clinical trials, before they are considered for regular clinical practice. This holds true for other parts of the eye such as retina, lens, optic nerve damage etc.
Is there scope for using this in the treatment of some of the major causes of defective vision like cataract, diabetic or hypertensive retinopathy?
Cataract has a simpler surgical solution wherein the cloudy lens is removed and an artificial lens is inserted into the empty lens bag to restore vision significantly. This may not require a stem cell based solution. Similarly, for diabetic and hypertensive retinopathy, we have good medical, surgical and life style management procedures available to control disease progression and therefore cell therapy is not considered an option right now.
Like any other transplants, what is the rate of rejection?
For any cell-based therapy, the rejection rate is dependent on the cell source. If patient’s own stem cells are used, then the rejection rate is close to minimal or zero. This is true for autologous, limbal region derived corneal cell grafts we offer to patients at LVPEI. But if the cells are taken from another individual, we call it an allogeneic graft, there is a greater possibility of rejection in the absence of any treatment for immune suppression. This follows the same principle of immunological rejection as in large organ grafts. But many animal studies and Phase I safety trials in humans suggest that the eye is an immune privileged organ and allogeneic cells transplanted to the retina survived for long term without immune rejection. But this needs careful evaluation in more number of controlled trials before we make any final treatment decision.
How do you collaborate with doctors regarding this type of research and more importantly its application?
We work hand in hand with our clinicians. Clinical problems and the need for newer solutions to treat patients form the basis of our research questions. All translation oriented research projects will have equal involvement of both the basic research scientist and the clinician scientist at every level of our planning and execution. This unique situation at LVPEI is a bigger strength to address clinically relevant problems and to take the research outcomes from bench to the bedside, for the benefit of needy patients. Our basic research team works hand-in-hand with our clinical research team comprising of experienced retinal surgeons such as Dr Taraprasad Das, Dr Vivek Pravin Dave, Dr Subhadra Jalali and Dr Rajeev Reddy. Together, we aim to establish a treatment option for patients suffering from retinal dystrophies.
In the perspective of community ophthalmology, what difference does this make to the community as a whole? Is it cost-effective?
Stem cell therapy, per se, is perceived as an expensive treatment option. This can be partly attributed to the cost involved in cell preparation, safety evaluations and storage needs, expensive facility maintenance, surgical and medical costs. While off-the-shelf, commercially available, cell-based products in international markets are obviously too expensive, in-house developed adult stem cell therapy programmes can be tailor made for each patient at affordable cost. This has been true with the limbal stem cell treatment we offer for corneal surface reconstruction at LVPEI. About 50% of our patients benefitting by this treatment are from below the poverty line and were treated free of cost.
However, in case of technology intensive options such as the iPSC-based cell therapy programmes, it can be challenging to bring down the cost. The pioneering Japanese team have put up a massive programme to establish iPSC banks, which will open up the possibility of HLA antigen matched allogeneic cell therapy, similar to the way the bone marrow and cord blood stem cell therapy are offered. But, if eye proves to be truly immune privileged and allogeneic cell therapy becomes an option, there are positive hopes for taking such treatment to larger masses. This is mainly because such iPSC-based stem cell products can be made in large numbers and a single batch of cell preparations can be used to treat hundreds of patients. So, with allogeneic cell therapy, it is possible to bring down the cost of treatment and make it affordable to patients from all sections of the society.
All this needs a clear understanding on the therapeutic benefits of such cells to patients and their long-term safety. We are working hard to ensure this before moving forward to take it to the clinics.
Would you like to add something more?
Stem cells are great. They offer a lot of promise. Also, the hopes and hypes are very big. So, let us be aware that they are not a panacea for all disease conditions. It should be considered only for conditions where they are scientifically tested and proven to be safe and offer clear clinical benefits to patients. This public awareness is very important to curb illegal practices and the booming cost of stem cell therapies.
by Usha Nandini