The Indian scenario of rare Lysosomal Storage Disorders, diagnostic and treatment approaches

Considering the experience you have in the field of LSDs, please take us through your journey at the Royal Free Hospital, you are training and educating around LSDs, and the foundation of the LSD Center.

I started my haematology training at Hammersmith Hospital in the early 1980s. I was fortunate to have witnessed the birth of the molecular revolution. Ever since approximately 1982-83, we have been able to identify genes, and I began a research career at the Hammersmith Hospital studying genetics. Genetics was not only important to my work in haematology, where there are common genetic conditions such as haemoglobin disorders or thalassemia disorders, but it also facilitated the study of rare inherited disorders, such as the enzyme deficiencies that underlie LSDs. Molecular medicine has revolutionised our approach to the diagnosis and pathophysiology of these conditions. It has also laid the groundwork for new developments in treatment, for example, treatment with recombinant proteins such as enzyme replacement therapy. These treatments have been translated into cancer and other diseases, treatments that will take us into the future of stem cell transplants and cellular treatments, and of course, gene therapy. It is an exciting time.

Studies in Europe, the United States (US) and Australia suggest an overall birth prevalence for all LSDs of one in 5,000-8,000. Specifically, it could be higher in a couple of populations, such as the Ashkenazi Jewish populations, which show a frequency of one in 850 births for rare lysosomal Gaucher disease. Do you believe this number could be underestimated, and is this scenario expected to differ in Indian settings?

We think of rare diseases as being approximately one in 2,000. We then discuss orphan diseases or ultra-rare diseases, which might be one in 40,000. Gaucher disease is considered the most common form of LSD, one in 40,000, and is rare. However, in some populations such as the Ashkenazi Jewish people, the prevalence is one in 850, which is not rare. Even at one in 40,000, in India, this translates to an astonishing 20,000 given India’s population. Therefore, rare diseases may be individually rare, but, collectively, this is a major healthcare issue. In Europe, there are 30 million patients with rare diseases. This will translate to 100 million in India and 350 million worldwide. Therefore, we cannot ignore rare diseases and simply focus on diabetes, hypertension and cancer, ignoring the fact that there will be 1,000s of adults and children, particularly children, with rare diseases. Fundamentally, diagnosis is easy and straightforward. However, we need to consider raising awareness of the conditions to encourage people to think of these rare diseases.

How can we raise awareness among physicians regarding the diagnosis of rare diseases when patients approach them with common complaints such as neurological or gastrological complaints?

When a paediatrician assesses a child with failure to thrive, the child might be anaemic or suffer from fatigue, growth failure, bruising, bleeding, skeletal changes, enlargement of the liver and spleen, neurologic changes, epileptiform fits, myoclonic jerks, or muscle abnormalities. However, if we see a constellation of these abnormalities presenting to a pediatrician or family physician, often a haematologist, then, we must think beyond anaemia, thalassemia and leukemia, and think of these rare inherited conditions. Sometimes, there is a temptation not to think of them and to dismiss them with the attitude that there is no opportunity cost, as these are untreatable anyway. However, caution must be exercised. These diseases are treatable. And of course, if you cannot treat the condition specifically, by diagnosing the condition, you are empowering the patient, you are empowering the family and allowing them to be alert to the possibility that other family members either are affected or will be affected because these are inherited conditions.

India has also seen a rise in awareness in the last two decades among physicians, their societies, and patient advocacy groups, to collectively work towards a better path for rare disease patients. Do you believe this will contribute considerably to the understanding of the burden of LSDs in India?

Yes. We have statistics in Europe and the UK that it used to take five to 15 years to make a diagnosis of Gaucher disease or Fabry disease. We know this by interviewing the patients at our centre. However, we know from information, particularly in Spain and France, that the interval between the initial presentation and the ultimate diagnosis is shortening across Europe. I hope that the same will also be true in India.

What are the typical diagnostic steps and pathways and what challenges hinder timely diagnosis?

I think that awareness is critical. We have published surveys showing that these patients typically present with fatigue, anaemia, bruising, bleeding and skeletal abnormalities. They typically present either to a family physician or a blood specialist, but often to a paediatrician. Diagnosis is easy once suspected. There is no real reason to think that it is going to be any different in India, and an article published in The Lancet identifies that all of these storage disorders are seen in India. The genetic abnormalities are similar to those observed in other parts of the world. India is a tremendously diverse country, composed of many populations that are not only genetically diverse, but also socially and culturally diverse in terms of their educational attainment and financial capabilities. Therefore, the way these patients are present will be different in various parts of the country. When seeing children with enlargement of the liver or spleen, neurological abnormalities, bruising, bleeding, anaemia, and failure to thrive, we must consider these rare diseases and initiate an appropriate blood test. It could be a Dried Blood Test (DBS) to make both enzymatic and molecular diagnoses.

What are the differences in the journey of a patient in developed countries such as the UK versus emerging countries such as India and other Asian countries?

One of the things that we have been successful in doing in the UK is to establish Centres of Excellence (CoE) where these patients can be referred, assessed and treated. I am also aware that in India, the Indian Council for Medical Research (ICMR) initiated a working group focussed on LSDs. They started their work in about 2015 and findings were published in The Lancet very recently. Jayesh Sheth from Ahmedabad, the lead author, identified eight centres across India throughout the breadth of the country, including the All-India Institute of Medical Sciences (AIIMS). We have some famous pioneers of genetic diseases in India, such as Dr Verma at the Ganga Ram Hospital in Delhi. They are world-famous figures who have made huge contributions to understand these disorders and studying their prevalence in India. India already has centres for the diagnosis and assessment of these patients. The challenge is to develop multi-disciplinary centres for the treatment of these patients.

How is disease management here different from that in the western world? Do you think that multi-disciplinary awareness about these treatment options is more or less on the same scale in different geographical regions?

Treatment for orphan LSDs was initially based on enzyme replacement. There was often an inducement to the pharma industry to develop and market these treatments, which would otherwise be unfeasible as there are only a small number of affected individuals. These treatments are quite expensive – several crore rupees per patient per year – making them unavailable to most patients in India. In fact, most patients worldwide are also not able to access treatment unless there is a healthcare system that affords universal care or insurance systems, the way it is funded in the UK and European States. Compassionate programmes exist, whereby companies such as Sanofi, Takeda and Pfizer have made these enzymes available in India. Approximately, 250 patients across India receive these treatments for Gaucher disease. However, that is 250 out of an estimated 20,000, a tiny proportion. In addition, I do not think that enzyme therapy is the only and the best way forward in India. Small molecule treatments, such as substrate reduction, are also effective. With some patent protection for these treatments now falling away, generic therapies are starting to emerge. India is a remarkable hub for the production of generic treatments.

The Union Ministry of Health and Family Welfare recently drafted a national policy for the treatment of rare diseases. Two initiatives have been taken: creating a corpus fund of Rs 100 crore for diseases, including LSDs, and developing a crowd-funding online portal for applications in the treatment of funding. As a treating physician, how would you identify these gaps here?

These are important initiatives, and it is fantastic that the Indian government has this on its radar and has identified the treatment of rare diseases as a priority. In terms of the actual delivery of these treatments, we must think outside of the box. We cannot allow the pharma industry to sell us enzyme replacement and substrate reduction at the price charged in Europe and North America. There are other approaches, and India has a history of incredibly talented physicians delivering high-intensity treatments such as stem cell transplantation. There are over 100 centres in India that provide stem cell transplantation. I believe that approximately one hundred centres in India provide liver transplants. We need to make these treatments safer to make them an appropriate way forward for metabolic and inherited diseases in India. Can gene therapy be used? Absolutely. These treatments are in trials worldwide. We need to encourage efforts to open these trials in India, making these trial genetic therapies available in India because there are going to be much more effective and cost-effective ways of treating these conditions in the future. Crowdfunding is of limited usefulness and needs to be channelled into research, developing specialist treatment centres, encouraging generic formulations of these small molecules, chaperone treatments and substrate reduction. Generic pharmacologic companies should be encouraged to manufacture these small-molecule products and generic formulations and make them available to the Indian population.

Point out some key recommendations that pharma companies and the government can make to improve the policy framework for rare diseases.

A practical approach for pharma companies is to encourage the manufacture of generic approaches with small molecules, substrate reduction and chaperones. Raising awareness of these treatments is imperative for pharma companies and their medical communication partners. The government, on the other hand, needs to encourage patient empowerment. Patient associations, for example, the LSD Support Society in India, and other rare disease organisations need to be supported and empowered because patients and caregivers can then encourage government funding. Importantly, we need to consider the stigma that often surrounds inherited conditions and the guilt that parents feel when bringing affected children into the world. We must confront the complicated issue of consanguinity, whereby inherited conditions become more common within a pedigree. If there is consanguinity within that pedigree, again, by empowering patients with the diagnosis, we can begin to approach these difficult areas and reduce that stigma.

There is a tremendous scope of awareness elevation for rare lysosomal disorders. Diagnosis for LSDs is not difficult, but needs appropriate and timely consideration. Alternate treatments, especially generics, are recommended to ease the burden of disease and provide cost-effective treatment to resource limited countries such as India. Ultimately, the patients need to be educated and empowered to approach the challenges associated with rare LSDs.