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Duchenne Muscular Dystrophy: How a self-taught dad is using state-of-the-art science to save his son

Ambrish and Nikita Kapadia

Physician-scientists are perhaps some of the busiest people on the planet. With heavy clinical duties on top of running a successful research program that involves keeping track of latest developments in their field, hiring and training research staff, planning and executing the research, and competing for research grants, these busy-bodies haven’t a moment to spare. So, if some of the top physician-scientists are spending time to share their clinical protocols with you, organize meetings in your honour, chalk your itinerary and take you out for dinner when you visit them, you must be a top scientist yourself, if not a prospective Nobel laureate. If you are none of these, however, you must then be Ambrish Kapadia!

In high school Ambrish quite enjoyed Biology and even contemplated a career in medicine. But due to severe myopia he was discouraged from pursuing it and settled, instead, for studying commerce. It made sense, as the family had a flourishing garment export business in Mumbai, and Ambrish joined it soon after completing college. Running an established business gave him time to pursue his passion of vigorous outdoor activities, especially water sports. He was cruising along comfortably, in the warmth and security of a joint family and the company of his lovely wife Nikita.

9th May, 2007 - Ambrish and Nikita welcomed their first baby, a boy - such a bundle of sheer joy that they named him Khush. Baby Khush was perfectly normal at birth and was reaching all his milestones till 12 months. He was the centre of attention for the whole family and his smiles and laughter brightened up their lives. While Ambrish and Nikita were totally taken in by the charms of baby Khush, it was the experienced eye of Tukaram, their helper who had taken care of two generations of the Kapadia babies, who noticed that Khush was developing some mobility issues. He was not very stable while sitting and crawling. However, the paediatrician had not rung any warning bells, and babies do vary in their development trajectory- so no one was unduly worried. Another few months elapsed until it became obvious that Khush, indeed, had weaker muscles than expected.

October 2008 - The paediatrician now asked to get a blood test done for creatine phosphokinase (CPK), an enzyme whose levels rise in response to muscle damage. The report showed highly elevated levels of CPK. The worried paediatrician told the unsuspecting parents, “Go see a neurologist. I hope what I am thinking is wrong….”. Khush was then taken to Bombay hospital and examined by Dr. Viraj Sanghi. He suggested to get a PCR test done for dystrophin gene, from Reliance Labs. The test was performed for 18 exons and showed that Khush lacked exon 52 of his dystrophin gene. The diagnosis was what the paediatrician had dreaded - Duchenne Muscular Dystrophy (DMD).

Khush Kapadia in August, 2008


What is DMD?

Treatment of DMD


Oct. to Dec. 2008 - For parents the cruelty of DMD diagnosis is that it comes with that helpless look in the Doctor’s eyes that there is basically little medical help for the baby. Ambrish and Nikita learnt from Dr. Sanghi that the only treatment to suppress some of the symptoms of DMD was steroids, which could not be administered to such a small baby. They would need to wait for Khush to grow older. But the disease would progressively worsen, which meant to Ambrish that time was not to be lost, and he must explore all possible avenues to save his darling child. This mission gripped him so strongly that till today it is THE primary purpose of his life. In fact, he did not grant himself the indulgence of depression or grieving because that would snatch away productive time. The first thing he did was to visit other top neurologists in Mumbai - Dr. Udani, Dr. Khadilkar; all said the same thing. Nothing can be done for such a small baby. But many prospective therapies are under trial for DMD in the USA, and they should join the US-led patient group - Parent Project Muscular Dystrophy (PPMD) to keep abreast of latest developments. Indeed, some parents in Mumbai had recently come together to form a PPMD-Mumbai group, and Ambrish became an active member of it. Through the PPMD-USA group Ambrish learnt about Dr. Jerry Mendell who was working on a gene therapy drug for DMD.

At the Guru’s feet : Private DMD tutorial from Jerry Mendell

To place matters in perspective, Jerry Mendell is one of the top experts in gene therapy and is considered the pioneer in developing gene therapy drugs for DMD. He is a Professor of Neurology and Paediatrics at Nationwide Childrens’ Hospital, Columbus, Ohio in the USA. Early in his medical career, in 1969, he saw his first DMD patient, at a time when the gene behind the disease was not yet identified. Today he is the lead Scientist behind Sarepta’s most promising gene therapy drug for DMD.

In November 2008, Ambrish contacted Jerry Mendell by e-mail and sent him the 18-exon PCR test report of Khush. Mendell asked for a more detailed test using MLPA, which could only be done at Gangaram hospital in New Delhi. On 26.11.2008, the day terrorists struck in Mumbai, Ambrish and his family were at Gangaram hospital for the MLPA test. The report came in 15 days and showed a deletion of exons 52 to 54. With this report Jerry Mendell was agreeable to put Khush on his ongoing gene therapy clinical study, but there was a hitch. They were not recruiting children younger than 5 years; hence Khush was not eligible. Although disappointing, the positive fall-out was that by then Ambrish had exchanged so many e-mails with Mendell that a bond had developed between them. Mendell was obviously struck by the sheer commitment of this dad to learn the science behind DMD.

During the day Ambrish took care of running his garment business, and at night he scoured through all internet sources to try and find answers to the zillion questions about DMD swirling in his head. Who better to learn from than the master himself- Jerry Mendell. Due to the time difference the moment Ambrish posted his nightly queries, the response from Mendell would be instantaneous. Questions like - “How will you reduce the size of dystrophin gene (micro-dystrophin) and yet retain its activity?” Answer from Mendell - “We will retain the two ends of the gene which work like a shock absorber, and keep the expressed protein connected to the sarcolemma (the cell membrane)”.

Question - “Will this truncated protein be recognized as foreign by the immune system and raise an immune response”.

Answer - “Yes, you are right. That is why we are giving steroids, and also considering plasmapheresis – (procedure to remove antibodies). In addition, we are including children in the trial who naturally have exon deletions in the region we are deleting to make the truncated synthetic gene; hence the micro-dystrophin protein may be less immunogenic in these children.

And so on, the tutoring continued!

Early 2009 - If the West cannot help, look East

Gene therapy, however promising, was still out-of-reach for Khush, and other avenues had to be explored. Every night Ambrish would check PubMed to look for any and every study related to DMD. One day he came across a paper from China by Cheng Zhang of Sun Yat-Sen University, Guangzhou. They had reported very encouraging results with a 12-year old DMD boy who had been administered umbilical cord blood transplant. They found that dystrophin-positive muscle fibers could be detected after 3-4 months, and there was functional improvement in upper and lower limbs of the child. Ambrish immediately tried corresponding with Cheng but this time language became a barrier. An interpreter was needed. Through word-of-mouth Ambrish found Atul Bhat who lived in Guangzhou and knew Chinese. In March 2009, Ambrish travelled to Guangzhou, and with Atul’s help he could communicate with Dr. Cheng. Ambrish learnt that Cheng had applied his method on 6 patients, with positive results. Could he try it on Khush? Well, he needed Khush’s HLA report. Ambrish was stumped. What was HLA? He had never heard the term. But that was not a problem. He immediately started reading up about it!

Back in India, he found out the best place for HLA typing, and got the test done from Histogenetics in Chennai. In April 2009, the whole family travelled to Guangzhou with the HLA report. Could the Doctor now try out his technique on Khush? Well, the technique was pretty harsh - it first involved destruction of pre-existing bone marrow cells by myeloablation drugs, followed by introduction of cord blood cells. The Chinese Doctor wasn’t very keen to try it on such a small child and that too not a Chinese national. Besides, Ambrish had his doubts as he received no convincing reply to his query as to why a blood transplant should alter dystrophin expression in muscle. So, the family returned to India without any treatment.

Pursuing blood transplant in India

If the cord blood transplant held even a remote promise for DMD, Ambrish was not giving up without finding out. He contacted haematologists and immunologists in Mumbai and came upon a public awareness seminar by Dr. Purvi Shah who was working for Stemcyte (India), a company that banks and provides cord blood stem cells internationally. After the seminar, Ambrish showed Purvi the Chinese study, but she was sceptical about the approach. Rather, she advised him to contact Dr. Joanne Kurtzberg who was the world-renowned expert on cord blood transplantation.

On the phone everyday with Joanne Kurtzberg Dr. Joanne Kurtzberg is a distinguished Professor of Paediatrics at Duke University Medical Centre, USA. She is the world leader in the use of cord blood transplantation to treat children with cancer, immune deficiencies, and a range of blood disorders. Ambrish promptly emailed her. Something about the sincere and desperate, yet profoundly intelligent tone of his mails struck a chord yet again, and the very master of the field was ready to engage with him in long dialogs. She told him that, in deed, she had done a transplant on a DMD boy who was suffering simultaneously from another inherited disorder called chronic granulomatous disease (CGD). Patients of CGD have defective immune cells, and are prone to life-threatening infections. Joanne had done the transplant to relieve the CGD symptoms in the child, but she found that for unknown reasons it seemed to help his DMD symptoms as well. So, would Joanne be able to do the transplant for Khush? Well, no. Because she could obtain ethical clearance for blood transplant only for patients suffering from disorders in hematopoiesis (related to generation of blood cells). DMD, in the absence of a blood disorder, would not qualify.

The next thing then was to look for a clinical hematologist in India who could possibly do the transplant for Khush. Ambrish contacted Dr. Sameer Melinkeri working at the Deenanath Mangeshkar hospital in Pune. Dr. Sameer got his hematology specialization at India’s topmost medical centre, CMC, Vellore and is an expert in bone marrow transplants. He explained to Ambrish the risks of doing a blood transplant since the body’s own immune cells are destroyed by harsh chemotherapy drug treatments before re-populating with the transplanted blood. Ambrish then told Sameer about his conversations with Joanne Kurtzberg who had indirectly treated a DMD boy. Sameer was left nonplussed. “Joanne Kurtzberg! She seldom replies to emails sent even by doctors… you’ve been talking to HER on her personal phone.” Well, Ambrish arranged for Sameer to talk to Joanne, and she graciously shared her detailed clinical protocol which Sameer could replicate if he wished! The decks seemed to be cleared; but weighing the cost-benefit-risk of the procedure, Sameer advised against proceeding with the transplant for a two-year old child.

Yet, Ambrish has not totally given up on this potential therapy for DMD. He found that Dr. Velu Nair at the Army-Navy hospital in New Delhi had done a bone marrow transplant for a DMD boy suffering simultaneously from Diamond Blackfan anemia. Ambrish is in touch with him, as also with Dr. Cheng and Dr. Joanne. None of them have followed up with their patients- so how much the treatment helped with improving dystrophin levels remains unknown.

Khush in 2018 Exon-skipping therapy for DMD Amongst rare genetic diseases, DMD is relatively more common and the maximally researched. Many therapeutic options are being tried for this disease world-wide. In 2010 Ambrish learned about the great therapeutic potential of exon skipping technology that allows a small amount of functional dystrophin to be produced in a DMD child. While this does not alleviate all symptoms of the disease, it can potentially result in a milder form of the disease, improve the quality of life, and increase longevity. Once again, Ambrish learnt about this technology from the scientist at the forefront- Dr. Annemieke Aartsma-Rus. She is a Professor of Translational Genetics at the Leiden University Medical Center, Netherlands, and is one of the pioneers of antisense oligonucleotide (ASO)-mediated exon skipping therapy for DMD. When Ambrish contacted her, they were conducting a clinical trial for skipping of exon 51. However, Khush was not eligible for it as in his case the skipping of exon 55 would be needed. Nevertheless, Ambrish communicated regularly with Annemieke and she shared the results of their trial with him. Eventually, the trial was stopped as the 2ʹ-O-methyl phosphorothioate ASOs being used by them contained thiol groups which produced toxicity. There were many adverse events amongst the patients on the trial. ASOs based on a different chemistry- phosphorodiamidate morpholino oligomers were then developed and the toxicity issue was resolved. However, their efficacy in improving dystrophin levels in muscle tissue is still low. Currently this is therapeutically the most advanced technology for DMD, and several ASO drugs for skipping of exon 51 (Eteplirsen), exon 53 (Golodirsen, and viltolarsen), and exon 45 (casimersen) have been approved. However, their clinical benefit is still to be confirmed. Their low efficiency seems to be due to poor uptake by muscles, and no uptake by heart muscles. The next generation of ASOs would be designed to overcome these challenges. However, for Khush to benefit from this technology, he would need ASOs that skip exon 55. Similarly, many other DMD boys would need customized ASOs to serve their individual needs. While this may happen in the future, at present children like Khush do not stand to benefit from ASO treatment.

Sphingosine phosphate lyase An outside observer, by now, could expect a sense of hopelessness arising in Ambrish after so many failed attempts at finding a treatment for Khush. But Ambrish knew better. His nightly scouring of the scientific literature had shown him that there was much to be explored, and the right treatment for Khush may be lurking around the corner, waiting to be recognized.

In 2011, during his study of the literature on muscle damage and how to reverse it, he came across papers that showed that sphingolipids (a class of fat molecule present in our cells) are active in muscle development. The sphingolipid called sphingosine-1-phosphate (S1P) promotes muscle cell survival and regeneration of new muscle cells upon damage. S1P levels are controlled by the enzyme sphingosine-1-phosphate lyase (SPL), which breaks S1P down. Hence if SPL levels rise, S1P levels drop, which results in defective muscle development and loss of muscle cell integrity. These studies were done in the fruit fly Drosophila and in mouse cell lines, and did not involve DMD. Ambrish wondered whether S1P levels were elevated in DMD muscle as well, and whether bringing them under control could be a strategy to stall muscle damage and promote regeneration. He decided to find out. One of the scientists publishing actively in this field was Dr. Julie Saba. She had published a paper in which she had inhibited SPL in a DMD model of the fruit fly Drosophila, and the result was S1P upregulation. This increased muscle satellite cells by two-fold and improved the strength of flight muscles. Having perfected the art of engaging with the scientists one-on-one, he shot off an email to find out if she had considered looking at the levels of S1P and S1P lyase in DMD patients.

Julie Saba is a distinguished Professor of paediatric oncology at University of California, San Francisco, USA. In 2011 she was at the Children’s Hospital Oakland Research Institute, California. Julie was so impressed with Ambrish’s insightful queries that it started an email friendship between them that lasts till date. Julie agreed to test the serum of Khush and other DMD boys for levels of S1P and the lyase enzyme in samples that Ambrish sent to her by FEDEX. Nothing conclusive came out from this analysis, but it induced Julie to look systematically at DMD in addition to her other major projects. Now her work on DMD has shown that the SPL enzyme is present at very low levels in normal muscle but its levels are highly elevated in damaged muscle fibers of both human DMD patients and in the mouse model of DMD (mdx mouse). Further her work shows that feeding the mdx mice with an inhibitor of the SPL enzyme very early in life, before and after birth, could reduce muscle inflammation and degeneration. These are really encouraging observations that have the possibility of getting translated into a treatment. Ongoing research will reveal their potential.

Although Julie and Ambrish were in regular contact since 2011, they first met only in 2019 when Ambrish visited her lab in San Francisco. In his honour Julie organized a conference where she invited various researchers working on DMD. She planned his itinerary so that he could make the most of his California visit. She arranged his meeting with some of the top Scientists like Craig McDonald at UC Davis involved in gene therapy clinical trial of DMD; and Niren Murthy in the lab of Nobel laureate Jennifer Doudna at UC Berkley working on CRISPR-Cas technology for treatment of rare genetic diseases!

Childrens day celebration, Physio Department, Saifee Hospital, 2017 Heart failure is a major cause of early death in DMD. What could be done to prevent heart damage? Time and again Ambrish had asked himself this question. While the progressive weakening of skeletal muscles caused disability in DMD, weakening of heart muscles (cardiomyopathy) caused death. Could there be ways to protect the heart before damage became life-threatening? In August of 2011, in his daily PubMed searches Ambrish saw a paper that suggested help could be at hand. This new study was titled “Early Treatment with Lisinopril and Spironolactone Preserves Cardiac and Skeletal Muscle in Duchenne Muscular Dystrophy Mice”. Immediately Ambrish set to work reading and comprehending the paper. Loads of questions arose in his mind- some could be trivial to a specialist, but all had the flavour that emerges only from a fresh mind that has just grasped a new subject. As usual, he emailed all his queries to the lead author, in this case Dr. Subha Raman, a professor of cardiovascular medicine at Ohio State University, USA. As usual, Dr. Subha was hugely impressed. In DMD patients the heart muscle cells are progressively damaged and replaced by fibrotic tissue which makes the heart muscles stiffer and less capable of pumping blood. It was already appreciated that this myocardial fibrosis sets in much before functional cardiac impairment can be detected in DMD patients. In recognition of this fact Dr. Subha Raman’s lab investigated whether early administration of anti-fibrotic drugs could attenuate cardiac disease in the DMD mouse model. The results of this study were highly encouraging. The question was: can they be tried on human patients. The drugs in question were already in use for the treatment of high blood pressure and heart failure in humans. So, the pharmacological properties and toxicity issues were well known. But they could not be prescribed to DMD patients who had not yet developed any clinical symptoms of cardiac fibrosis. On the other hand, the study showed that benefit in the mouse model accrued only when the anti-fibrotic drug was administered early on. It was, however, not ethical to give the drug to patients who did not yet have symptoms of fibrosis, without the validation of a clinical trial. Dr. Subha was planning to initiate such a trial if the funding was in place. Ambrish was impatient. Clinical trials typically take many years. By then it could be too late for Khush as fibrosis would have already set in. Dr. Subha had no shortcuts, but she agreed to share her protocol with Ambrish, if it could be used by Indian Doctors for DMD patients. Armed with the protocol, Ambrish met Dr. Ashwin Mehta, a cardiologist who had been treating Ambrish’s father for his heart ailments. Since the drugs were well known, Dr. Mehta said he could prescribe them for Khush, but only if there was some evidence of myocardial fibrosis. Imaging by echocardiography was not suitable as it does not provide any evidence until the damage is well advanced. The need of the hour was to find a method, a biomarker for early, asymptomatic cardiac fibrosis.

With his antennae capturing even the faintest signals, Ambrish read a newspaper report about a just-concluded marathon in Mumbai where several runners had unfortunately died due to fibrosis of heart muscles. The report mentioned that they had suffered a heart attack and the levels of Troponin T and I in their blood were very high. Troponin T and I are proteins present uniquely in heart muscle cells. Under normal conditions they are present in very low amounts in the blood. However, when there is damage to heart muscles, as in myocardial infarct, these proteins leak out from the cells into the bloodstream. Thus, their presence in the blood indicates heart muscle damage. Immediately Ambrish took a blood sample of Khush to get troponin testing done in a private lab. Sure enough, his troponin levels were high, even though he was barely five years old. What was this if not direct evidence of heart muscle damage even though fibrosis was not visible?

With this evidence it was now possible for Dr. Mehta to prescribe the combination drugs (an ACE-inhibitor, and an aldosterone antagonist) used by Dr. Subha. He contacted a paediatric cardiologist, Dr. Bharat Dalvi to recommend dosing for paediatric patients. Khush, along with a few other DMD patients in Mumbai became perhaps the first children, in 2012, to be given Losartan and Eplerononeroutinely. This protocol was later taken up by Dr. Kshitij Sheth, apaediatric cardiologist at SRCC Children’s Hospital in Mumbai. Thebenefit of these drugs was obvious as the troponin levels in these children returned to normal. Ambrish was way ahead of his time, aschildren in the USA started getting these drugs only in 2018 after the completion of clinical trials. Currently these drugs have been included in the standard of care for DMD children. Another fallout of this effort by Ambrish was the introduction of cardiac MRI (a far more sensitive test) instead of echocardiography to look for heart muscle damage routinely in DMD children. Unfortunately, not many places in India have the expertise to perform cardiac MRI. Very few radiologistslike Dr Himanshu Chaudhary (who was motivated by Ambrish) are performing cardiac MRI on DMD boys at Sir HN Reliance Foundation Hospital in Mumbai.

Emanating from the 2011 study from Dr. Subha’s lab, Ambrish had worked his way to provide Indian DMD boys with some relief from cardiac damage. Little wonder then that finally when Ambrish visited Dr. Subha in 2018, she treated him like family and took him out for dinner, leaving Indian doctors perplexed. How did she find the time? She was otherwise so busy; they could barely get an appointment with her!

Khush at NASA, 2023 Prof. Dariusz Górecki (Darek) - The Purinoceptor Guru

The latest of Ambrish’s eminent Gurus is Darek, Professor of Molecular Medicine and Director of Research at the School of Pharmacy and Biomedical Sciences, University of Portsmouth, U.K. Darek’s special interest is a class of protein molecules that exist on the cell surface and are called receptors since they can bind (or ‘receive’) molecules in the external environment of the cell and guide the cell to react appropriately. Each receptor class is specific to a particular class of molecule that it can perceive and bind. The receptor class Darek works on is called purinoceptor (P2X7) since it binds to a class of molecules called purines. So how is this related to DMD?

One of the most important purine-related molecules in the cell is adenosine triphosphate (ATP) which is the cell’s energy currency and is essential for cellular function. In DMD muscle cells, on the one hand ATP production comes down, and on the other hand there is leakage of ATP to the outside environment (the extracellular matrix) due to damage of the cell membrane. Once leaked, this extracellular ATP can now bind to purinoceptors on muscle cells, and on other types of cells like those of the immune system, and glial cells of the brain. Binding of ATP to P2X7 receptors on muscle cells triggers cellular dysfunction and death. In the case of immune cells this binding leads to chronic (sterile) inflammation that further contributes to the dystrophic pathology. Hence adopting a dual approach of preventing ATP leakage by preserving membrane integrity of muscle cells, and blocking P2X7 receptors from binding extracellular ATP could have a beneficial effect on preserving muscle integrity. Prof. Darek’s group has done very extensive research in this area and they demonstrate that, indeed, inhibition of P2X7 receptor alleviated both muscle and non-muscle symptoms in the mdx mouse model.

A potent blocker of P2X7 is a drug called Zidovudnine (azidothymidine, AZT), already in use as an anti-HIV drug due to its ability to inhibit viral reverse transcriptase. A short-term AZT treatment in mdx mice decreased inflammation in leg and heart muscles and there was recovery of muscle strength without detectable side effects. These encouraging results, coupled with the fact that AZT has a favourable pharmacological profile in children, makes it a very attractive candidate for treatment of DMD. Ambrish has been in touch with Prof. Darek for almost a decade ever since he came across Prof. Darek’s papers in this area. Their regular email exchanges have of course enabled Ambrish to understand the subject more accurately, they have also provoked Darek to consider his data from new angles. This has culminated in Darek’s visit to meet physicians in Mumbai (his first visit to India) in mid-January 2020.

Currently Ambrish is assisting Prof. Darek to initiate AZT clinical trials for DMD children in India.

Fast forward to the present : The crusade continues Amongst rare diseases DMD is one of the best studied and researched; yet its complexities are enormous and till date patients do not have a treatment option that can significantly increase dystrophin levels and stall or slow down disease progression. Nothing of any consequence, that could remotely impact DMD has escaped the attention of Ambrish. It is hard to enumerate the many studies which Ambrish has closely followed. From China, and Pakistan to USA, Europe and Australia, Ambrish has contacted hundreds of scientists whose work had any bearing, whatsoever on DMD. I briefly describe some of his achievements with Indian DMD children.

He has helped Doctors in India to conduct small clinical trials to deliver adipose derived mesenchymal stromal cells intravenously to patients. Two to three injections were given at 6-month to 12-month intervals. The results were encouraging, with children showing marked improvement in muscle strength. However, since MSCs can potentially differentiate into many different cell types other than muscle and they also secrete growth factors, it was not possible to continue with multiple injections without monitoring the fate of these cells in the body. It was important to understand whether the benefit seen in children was due to secretion of growth factors or increased dystrophin expression. This was difficult due to lack of standardised methods for measuring dystrophin levels in immunoblots.

Another innovative contribution of Ambrish was in trying out the drug Pirfenidone which is routinely used for treatment of pulmonary fibrosis. This drug works by inhibiting a major growth factor, called transforming growth factor- beta (TGF-β) that is responsible for promoting the formation of fibrous tissue. The same growth factor is also present in muscles of DMD patients and contributes to replacement of injured muscle cells by fibrous tissue. Ambrish rightly conjectured that if Pirfenidone was helping reduce lung fibrosis, it could have beneficial effect on reducing fibrosis in DMD muscle as well. However, the drug was mainly being used by pulmonologists to treat lung patients and had never been considered by neurologists as a possible drug for DMD. There was no good reason why that was so, and at last one pulmonologist Ambrish talked to agreed that this drug should be tried for DMD. It is a well-tested, safe drug, and Ambrish was able to convince a few Doctors in Mumbai to prescribe this drug to the DMD boys in Mumbai. Possible liver toxicity could be a major side effect of this drug. The liver profile of children on Pirfenidone is checked periodically to discount any toxicity. Here too, some innovation was needed. The commonly used indicators for liver function are the enzymes serum glutamate pyruvate transaminase (SGPT), now called Alanine aminotransferase (ALT), and serum glutamic-oxaloacetic transaminase (SGOT) now called Aspartate aminotransferase (AST). These enzymes are mainly present in the liver, and their levels in the blood are very low. When liver cells are damaged these enzymes leak out and their levels in the blood are abnormally elevated. It turns out that smaller amounts of these enzymes are present in muscle as well, and the persistent muscle damage as seen in DMD also leads to elevated ALT and AST levels in the blood. Hence, in DMD boys these enzymes are not a good indicator of liver toxicity. Rather, the liver-specific enzyme gamma-glutamyl transferase (GGT) is a better choice to determine liver toxicity in DMD since its level in muscle cells is extremely low. The GGT test is now being routinely used to check the liver profile in DMD patients.

Another avenue Ambrish explored was to reduce the steroid-induced osteoporosis onset in DMD boys. Steroids are the standard of care for these children to reduce inflammation, but prolonged steroid use and low physical activity predispose these children to osteopenia, that is low bone mineral density. This leads to bone weakening and fractures, and progression of scoliosis (spine bending). This aspect was not being considered in standard treatment of DMD children. Now bone density is tested routinely, and accordingly the bisphosphonate drugs Alendronate and Zoledronate are prescribed to the children. These drugs work by inactivating the cells called osteoclasts that break down bone tissue. This treatment is helping to contain the problem of osteoporosis. Thus, by being constantly vigilant about DMD-associated pathological symptoms Ambrish has been able to vastly improve the routine care that the DMD children presently receive. This helps to reduce disease progression and somewhat improve the quality of life.

Presently, Ambrish continues to evaluate all possible treatment options, including cell and gene therapy and CRISPR/CAS9-mediated utrophin upregulation, hoping that an effective, affordable drug becomes available for Khush and other DMD children before it is too late. After he joined PPMD - India, their team has initiated several indigenous research projects in India by providing funding and other support. These include 1) AAV-mediated gene therapy in collaboration with Narayan Nethralaya Foundation, Bengaluru under leadership of Dr Arkasubhra Ghosh; 2) CRISPR CAS-9 mediated utrophin upregulation in collaboration with Kalyani University, West Bengal, under leadership of Prof Utpal Basu; and 3) Allogeneic human ADMSC derived pre-myogenic cells conditioned with muscle differentiation chemical cocktail for DMD. This in vitro study was conducted at NIMS / ESIC Hyderabad.

This humongous effort by parents from their own personal funds needs to be saluted. Obviously Ambrish is not alone in this. They are a team of real-world heroes who have placed faith in Ambrish and provided him continuous support. These Mumbai- and Delhi-based parents are Rajesh Raythatha, Anand Shah, Faizan Gubitra, Jyoti Bharadwaj, Veenu Kohli, Dr. Aalok Maker, Nirmala Parab, Heena Pisal, and Neelam Devjani.

Living with DMD : Khush - a happy teenager Like any other kid, every morning at 8.30 am Khush heads for School, an integrated school for special needs run by the Aditya Birla group. Here they have special educators who are trained to teach children with Down’s syndrome, autism, and other such disorders. They do not have the concept of conventional classes; rather students are assigned to different levels depending on their proficiency. Currently Khush is in level C (equivalent of class 7 in a conventional school). The subjects he enjoys most are environmental studies and geography.

During lunch break at noon Khush eats with his mom, Nikita, who carries his lunch to school. Due to prolonged steroid use Khush has lost most of his taste buds and enjoys only plain, home-cooked food. Nikita waits for school to be over at 2.30 pm after which she takes Khush straight to physiotherapy and aquatherapy sessions. This regular physiotherapy and aquatherapy of an hour every day is very important for Khush to keep his muscles active. By the time they get back home after negotiating the Mumbai traffic it is past six in the evening. There are kids playing in the park at that time but Khush, unable to match their physical prowess, chooses to keep away. Rather he is happy at home watching his favourite TV programs on National Geographic, Animal Planet and news channels. Khush is quite unlike the average teenager. He needs physical support for some of his daily activities, but he makes no further demands of his parents. He has learnt to be self-sufficient and can keep himself entertained. When they go shopping, he never throws any tantrums and is content with whatever his parents buy for him. Peoples’ remarks about his appearance don’t bother him in the least. By thus reducing his wants and shunning negativity, Khush spins a beautiful universe of his own in which happiness is continually created and preserved and conflict is destroyed. He, the creator of happiness, fully justifies his name. The pain of physical disability is completely subsumed in this all-pervasive happiness.

Living with DMD: the parents’ perspective The slow physical decline and increasing dependency for daily living is a source of hardship for the average DMD child. For the doting parents it is even more tortuous to see this progressive deterioration in their beloved child. Both Ambrish and Nikita went through massive depression in the early days of Khush’s diagnosis. Ambrish could slowly recover from it as he fully immersed himself in trying to understand the disease biology and ways to treat it. Now he is so involved in keeping abreast of latest developments and constantly acquiring knowledge about DMD that he has little time to brood or bemoan his fate. However, Nikita has not been so fortunate. She still has clinical depression and takes medication. Her world is her son, and as she sees him slowly lose the ability to perform tasks he could do earlier, it breaks her heart. Her only solace is the company of other DMD moms who are going through the same journey and understand her completely.

Khush at school with his teacher My tribute to Ambrish, a person of rare intellect True intellect, according to Bhagvad Gita is the ability to grasp the essence of any knowledge, and leave out the non-essential. By this definition, Ambrish is a rare intellectual. He has put to practice the essence that he has grasped, which is the real nature of ‘buddhi’. The rare disease community is blessed to have an individual of his courage, commitment, and calibre.


J.J. Brown
J.J. Brown
Sep 08, 2023

Thank you so much for this inspiring record of heroism and international cooperation. I am astounded by the dear parents' perserverence and success in getting the best possible future for their child.


Rama Boddanapalli
Rama Boddanapalli
Jul 10, 2023

Thank you Sudha ji for this wonderful inspiring blog about Mr Ambarish Ji .

We from DMD community always look upto him .He is an SME for all parents .


Parent of DMD kid

BharathMD foundation


Agree with Kalyani Menon and others


Shalini Urs
Shalini Urs
Jun 21, 2023

Truly inspiring, touching, and a beautiful story. I wish and pray that Khush, would get better and (with all these advancements in medicine) and crusaders like Ambarish and others will surely push the boundaries of treatment for DMD and other pathologies. May the force be with Ambarish and the compassionate medical community.


gitika khanna
gitika khanna
Jun 18, 2023

This is a phenomenal story of astounding efforts put by Ambrish along with his fellow parents..Am one of those who have been fascinated by the wealth of knowledge acquired by him in context to MD. I strongly hope n wish that Khush and many other DMD kids get a treatment well in time.

Best regards

An LGMD warrior,

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