Author: <span>Ashok Vellodi</span>

Research methodology workshop at CMC Vellore, 28th October 2022

This was my second visit to the Christian Medical College, Vellore (https://www.cmch-vellore.edu/). I was a guest of Professor Sumita Danda, Professor and Head, Department of Genetics. We had decided to conduct a research methodology workshop.

I arrived in Vellore from Chennai the previous day. I was put up at the Alumni Guest House. This is situated in the beautiful Bagayam campus, which is the residential campus and is situated 6 km south of the main hospital in Vellore.

In the afternoon I was taken on a tour of the main hospital, including of course the department of genetics, by Dr Mrinalini Peters, Assistant Professor in Medical Genetics, and Sanjana Daniels, a final year MD (Paediatrics) doing a peripheral posting in Medical Genetics. Vellore is renowned for delivering high levels of care despite immense pressure on beds and staff. The main hospital accommodates all the core specialities. In June this year a new 1,500-bed hospital was opened in Ranipet district by Kannigapuram village. Most of the super specialties eg neurology, cardiology, bone marrow transplant have all moved there. This has considerably reduced the overcrowding in the main hospital.

The workshop was held the next day at the Aavana Inn, just across the road from the hospital, which facilitated easy access from the hospital. The workshop was divided into two sessions. The morning session focused on case presentation skills, while the afternoon session was devoted to manuscript writing and critiquing. At the end of each session, I gave a short talk relevant to that session. Prizes were then given for the best presentation and paper.

The workshop was well attended and feedback was good, although ideally we could have done with an extra day. Still, it was a good start, particularly bearing in mind that it was the first time for me!!

Below are some pictures from the workshop.

Professor Danda presenting the case report presentation prize to Dr Manish Madhai Beck

Professor Danda presenting the manuscript prize to Dr Peters — Professor Danda presenting the paper presentation prize to Dr Mrinalini Peters

Workshop attendees with Professor Danda and myself

Visits to Kolkata Hospitals 19th October 2022

I visited several hospitals in Kolkata on 19th October. This was something I had always wanted to do, but the opportunity had never presented itself. I’m very grateful to Dr Dipanjana Dutta, Genetic Counsellor at the Institute of Child Health, and State Coordinator for the Organization of Rare Diseases India (ORDI), for organising my visits to the centres. Although my visit was in an independent capacity, not sponsored by ORDI, Dipanjana gave unstintingly of her time.

As with much of India, healthcare in West Bengal features a universal healthcare system, run by the state and central governments. The Ministry of Health & Family Welfare of the Government of West Bengal is responsible for administering and funding the public hospital system in the state. The entire state population is covered by a health insurance, either provided by their employer or the Employees’ State Insurance (ESI) scheme. Other categories of people (low-income, self-employed, the unemployed or the retired etc.) are covered under the state’s public health insurance scheme (Swasthya Sathi).

We first visited the Institute of Child Health, the premier children’s hospital in Kolkata and the first of its kind in India (https://www.ichcalcutta.org/). We met Dr Apurba Ghosh, the Director of the Institute and the doyen of paediatrics in Bengal. Dipanjana took me around the hospital, and we then went to the lecture theatre where I gave a talk on the clinical management of mucopolysaccharidoses.

From the ICH we went to the Institute of Fetal Medicine (https://ifmkolkata.co.in/), where we met Dr Kushagradhi Ghosh, Consultant in Fetal Medicine. Dr Ghosh has a well-established setup in a purpose-built building that is ideal for a multidisciplinary team or clinic. It would be very suitable for an LSD MDT clinic. Dr Ghosh was very receptive to the idea and certainly this is something that should be pursued.

Our last stop was at Apollo Hospital, were we met Dr, Anjan Bhattacharya, a developmental paediatrician, and his colleague, Dr Tamal Laha. Dr Bhattcharya has established a service for children with autism and cerebral palsy over the last 15 years. He heads a multidisciplinary team of physiotherapists, occupational therapist and speech and language therapists, and vision therapists. Every child who is referred is carefully assessed over a period of 7-10 days, at the end of which a comprehensive report is produced for the parents. This is an outstanding model of a multidisciplinary team, and its principles can be applied to other areas, including of course LSDs. Dr Bhattacharya is planning to roll this out to other Apollo hospitals around the country.

Of the three hospitals we visited, the Institute of Child Health is run by a trust, and Apollo is of course private. However, both are covered by the Swasthya Sathi, so patients having this get free treatment. The Institute of Fetal Medicine is classified as a nursing home and is not covered.

Unfortunately I was unable to visit any of the government hospitals, such as the Institute of Postgraduate Medical Education and Research and SSKM Hospital, which has been designated as a Centre of Excellence under the National Rare Diseases Policy. This was largely due to bad timing on my part; I had opted to visit during the Durga Pooja festival, and a lot of staff were on holiday. Hopefully I will get the chance to go back some time.

National Symposium on Genetic Diseases, New Delhi, 15th-16th October 2022

It was wonderful to be able to come to India again after nearly three years of Covid-induced absence, to meet old friends and make new ones.

The National Symposium on Genetic Diseases was aimed at reinforcing established ideas and concepts, while introducing new ones. It was organized by the Rare Diseases India Foundation (RDIF). The organising committee consisted of Mr Saurabh Singh, Co-founder, RDIF, Lt. Col. Aradhana Dwivedi, Medical Geneticist and Assistant Professor, Army Hospital Research and Referral, New Delhi, Dr Veronica Arora, Consultant Clinical Geneticist and Assistant Professor, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, and myself. The sponsors were Lifecell Diagnostics, Redcliffe Labs, Takeda, Medgenome, Sanofi, Lilac Insights, Genetico, Dr Lal Pathlabs and Genes2Me.

A critical component of the symposium was a workshop, organised by Veronica, Aradhana and Dr Sameer Bhatia from Sir Ganga Ram Hospital. The workshop was preceded by lectures covering basic aspects of genetics and genetic testing.

The symposium was inaugurated by Prof I.C, Verma, Senior Consultant and Head, Department of Medical Genetics, Sir Ganga Ram Hospital, New Delhi.

The first session featured a guest lecture by Prof Vivek Jha, Executive Director, George Institute for Global Health, India and Professor and Chair of Global Kidney Health, Imperial College, London. He spoke on nephrogenetics, drawing attention to the similarities with other rare genetic diseases.

The second session focused on LSDs. In addition to basic cell biology and molecular genetics (Dr Sunita Bijarnia-Mahoy and Dr Neerja Gupta), the challenges of making an early clinical diagnosis were highlighted, and possible solutions involving innovative tools such as AI explored (Dr Ashok Vellodi). The diagnosis and management of Gaucher disease was described, with a focus on new directions (Dr Mamta Muranjan).

In her keynote lecture, Prof Phadke presented an overview of the two major forces in India’s genetic landscape; endogamy and consanguinity.

Prof Arndt Rolfs, live streaming from Germany, presented a new technique for whole genome sequencing and made a compelling case for its inclusion in the diagnostic armory for rare diseases.

The second session featured five talks covering the entire gamut of genetic diseases and aimed squarely at its cutting edge, from preimplantation genetic diagnosis (Prof Seema Thakur) and newborn screening (Dr Rama Devi), to genetic manipulation in spinal muscular atrophy (Prof Shefali Gulati) and gene therapy (Prof Madhulika Kabra). A novel approach to diagnosis, that of artificial intelligence, was presented by Dr Harsh Sheth.

Full details of the programme can be found on the RDIF website

https://rdif.org.in/

Below are some pictures from the symposium

Therapeutic Options in MPS III

A thoroughly researched, detailed, up to date review of the current and potential future therapeutic options for MPS III. Well worth reading.

Summary of treatment options for MPS III 2020

Cellular and Gene Therapies Targeting the Central Nervous System in MPS Disorders

Accessing the CNS in MPS disorders remains elusive. Despite recent advances, significant challenges remain. However, some progress is being made.

This article provides a comprehensive review of recent advances, describing the challenges and how they might be overcome. Particular attention is paid to gene editing and base editing, and importantly how these therapies can be delivered to the CNS.

Cell and Gene Therapies for Mucopolysaccharidoses – base editing and therapeutic delivery to the CNS

For a more detailed review of recent advances in gene editing, here is a good recent review.

Sharpening the Molecular Scissors Advances in Gene Editing Technology

Biosimilars for Gaucher Disease

An interesting recent review article on this subject, highlighting the importance of defining a biosimilar. Worth reading.

http://gabi-journal.net/are-there-biosimilar-orphan-drugs-for-gaucher-disease-an-overview-in-mexico.html

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in MPS IIIA mice

A team from Stockholm (the Research & Translational Science Unit, Swedish Orphan Biovitrum AB) have recently published the results of a new approach to the treatment of MPS IIIA.

When recombinant enzyme is given intravenously, it is cleared very quickly by cells through their M6P receptors. So little or no enzyme is available for uptake by the brain. The Stockholm team modified the enzyme in such a way that its uptake by M6P receptors was blocked. So the enzyme remained in the circulation for much longer. The results were striking, with significant reduction in levels of heparan sulfate, lysosomal pathology, and inflammation. Importantly, clinical improvement was also seen in several areas.

This approach has been tried before, with limited success. However, the Stockholm team have introduced some important modifications, and their results are certainly superior.

While acknowledging that more work needs to be done, the results have been sufficiently encouraging; the company have now commenced clinical trials. The links are

https://clinicaltrials.gov/ct2/show/NCT03423186#contacts

https://clinicaltrials.gov/ct2/show/NCT03811028

Here is a link to the published paper

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in MPS IIIA mice

A potentially new therapeutic avenue for neuronopathic Gaucher disease; induced pluripotent stem cell infusion in a mouse model

The neurological features of neuronopathic Gaucher disease (nGD), like other LSD’s that affect the CNS, do not respond to ERT. In this paper, Peng et al treated a mouse model with intravenous infusions of iPSC- derived neural stem cells. The preparation used is able to cross the blood brain barrier. There were several beneficial effects of the treatment. Importantly, the levels of acid beta-glucosidase in the brain were higher post treatment and there was some neurological improvement. The authors point out that further work is needed before clinical trials are possible. There are also important challenges of iPSC therapy that need to be overcome. However, an important consideration is that, since no viruses were used, so this approach does not have the disadvantages of gene therapy using viral vectors.

Here is the paper

Intravenous infusion of iPSC-derived neural precursor cells in mouse model of Gaucher disease

Ten years of enzyme replacement therapy in paediatric onset Mucopolysaccharidosis II in England

Enzyme replacement therapy (ERT) for MPS II was licensed in the UK in 2007. Broomfield et al have just published a ten year follow up. This is the first significant review since the Hunter Outcome Survey (HOS) Registry data review in 2017, and adds some important findings:-

1. Cessation of ERT did not trigger a rapid decline (as was reported in the HOS study).

2. Certain features such as cardiac manifestations showed minimal response to ERT.

3. Perhaps most importantly, the neurological features showed a far wider spectrum than previously described. The previously accepted division into “severe” and “attenuated” groups seems to be no longer tenable.

Clearly this last point needs further investigation. The neurological features in MPS II need careful description and delineation, so that clinicians and families are better informed about outcome, and future trials of new treatments can be better designed.

Here is the full paper.

Ten years of enzyme replacement therapy in paediatric onset mucopolysaccharidosis II in England

A New Approach To Treatment of LSD’s; Messenger RNA (mRNA) Therapy

Messenger RNA (mRNA) is a group of molecules that convey genetic information from DNA in the nucleus into the cytosol of the cell. There, this information is used by ribosomes to make protein. So mRNA’s that make specific proteins can be constructed and inserted into a cell, which has the machinery to make the specific protein. This forms the basis of mRNA therapy.

Not surprisingly, the concept is not new, but early attempts were unsuccessful for several reasons. These are now gradually being overcome, and mRNA therapy has become one of the most exciting new therapeutic developments seen for many years, with a wide range of applications. For example, it can be used to make vaccines far more quickly and effectively. The possibility of anti-cancer vaccines is also being explored.

Importantly, mRNA therapy provides solutions to some of the drawbacks of gene therapy.

Here is a useful review of mRNA therapy.

Next-Generation Therapeutics mRNA as a Novel Therapeutic Option for Single-Gene Disorders

Monogenic disorders, such as LSD’s, are prime candidates for mRNA therapy. There has been very encouraging progress in this area. Earlier this year, researchers from Translate Bio, Shire Pharmaceuticals and Biomere successfully treated a mouse model of Fabry disease using mRNA therapy, using the liver as the source of enzyme. Here is their paper

Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as compared to ERT

It is probably only a matter of time before mRNA therapy is used to treat more LSD’s. For the time being, however, it is unclear whether it can be sued to treat LSD’s that affect the CNS. We shall have to wait and see.