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



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.


Cervical Spinal Cord Compression in MPS IVA; Clinical Signs In The Absence of MRI Changes.

Cervical spine instability is a well-known complication of mucopolysaccharidosis IVA (Morquio A disease). If left untreated it nearly always results in spinal cord compression  and progressive neurological deterioration. Timely surgery can be not only life-saving but may prevent  irreversible damage to the cervical cord.

MRI scan of the cervical spine can detect early cord compression, allowing surgeons to intervene early. It has become an essential part of monitoring MPS IVA.

In a recent paper, Broomfield and colleagues at the Royal Manchester Children’s Hospital have described their experience of cervical spine surgery in MPS IVA over an eighteen-year period. Their findings of course confirm previously reported experience as above. However, they also include six patients who developed clinical signs of cord compression in the absence of any MRI changes. This is an important observation and a timely message. It underlines the importance of careful clinical examination, as well as the danger of over-reliance on MRI scans.

Here is the full reference with the link to the paper (pdf kindly supplied by Dr Broomfield).

Outcomes from 18 years of cervical spine surgery in MPS IVA; a single centre’s experience. Broomfield, A., Zuberi, K., Mercer, J. et al. Childs Nerv Syst (2018) 34: 1705. 

CME on Lysosomal Storage Disorders, Fetal Care Research Foundation, Chennai, 18th and 19th May 2018

I was privileged to be part of this event, at the kind invitation of my friend and colleague Dr Sujatha Jagadeesh. The event was organised by the FCRF , and held at their new expanded facility at the VHS Hospital, Chennai. Support was provided by Sanofi Genzyme. The event was held over two days. The mornings were taken up with lectures on LSD’s. In the afternoon there was a teleclinic, in which the patient examination, description of physical findings and discussions, including discussions with parents, were all filmed and relayed audiovisually to the audience in the adjacent room. This allowed a large number of people to “sit in” and observe without upsetting or intimidating the families. The teleclinic was Dr Sujatha’s idea; so simple and yet so effective that one wonders why it is not done more often!!

Visit to AIIMS, New Delhi, 14-16 May 2018

I visited AIIMS New Delhi in May this year at the kind invitation of Prof Madhulika Kabra and Dr Neerja Gupta in the  Department of Genetics. As with  previous visits, this one consisted of clinics and lectures to the postgraduate and DM (Genetics) students. Here are some pictures with the staff and students


In addition, I was privileged to be involved with the MPS Day celebrations organised by the Lysosomal Storage Disorders Support Society (LSDSS) held on the 14th. The event included a highly successful multidisciplinary clinic. More information about this an(and pictures) can be found on the LSDSS Facebook page here. It also gave me the opportunity of catching up with my friends and colleages from the LSDSS, including Manjit Singh and Shashank Tyagi.

MPS II Update

There have been a number of interesting publications over the last year on MPS II.

Whiteman and Kimura (Shire Inc.) have written a comprehensive overview of the development of idursulfase therapy. Here is the full article

Development of idursulfase therapy for MPS II 2017

Muenzer et al reported the results of follow up of patients receiving ERT. Data from the Hunter Outcome Survey (HOS) was used for this purpose. A total of 639 patients (excluding females, those patients who had received HSCT, and patients enrolled in the phase 1/2 [TKT018] or phase 2/3 [TKT024] clinical trials) who had been followed up for at least 6 months on ERT were reported. Continuing improvements were observed in various visceral parameters. However, results of cognitive function were not reported. The authors acknowledge some shortcomings of this study. For example, collection of urine for GAG analysis is more difficult in patients with severe neurological involvement.

Here is the full paper

Clinical outcomes in idursulfase-treated patients with MPS II. 3- year data from Hunter Outcome Survey (HOS)

Burton et al report survival in MPS II patients. Again, their data is drawn from HOS. Two key findings are

  1. A 54% increase in survival in treated vs untreated patients
  2. A five fold higher risk of death in patients with cognitive impairment.

Here is the full paper

Survival in idursulfase treated and untreated patients with mucopolysaccharidosis type II data from the Hunter Outcome Survey (HOS)

These findings are not surprising, but they emphasise the need for early diagnosis of, and more effective treatments for, the brain involvement in MPS II.

Escolar et al reported a scoring system for early diagnosis of CNS disease. They found that seven early clinical markers and a severity score index of CNS involvement can be used for initial screening of children who might benefit from CNS-directed therapies. This paper has not received the attention that it should have; the severity score described should be more widely used.

Here is the full paper

Early clinical markers of central nervous system involvement in mucopolysaccharidosis type II

As far as treatment of brain involvement in MPS is concerned, Scarpa et al have written this timely review of recent developments in the field.

Here is their full paper

Treatment of brain disease in the mucopolysaccharidoses 2017


Teaching at SGPGI, Lucknow, November-December 2017

In November 2017 I was kindly invited to  SGPGI Lucknow by Prof Phadke, Head of the Department of Medical Genetics, to teach on the DM (Genetics) course. This was my second visit to SGPGI this year. This was a more intensive session than my previous visit, extending over a week, and consisting of several lectures and clinics. The lectures covered various aspects of LSD, from basic science to new treatments. While they were specifically designed for the benefit of the DM students, the lectures were attended by PhD students as well. It was also possible for the lectures to be telecast live to other centres, thanks to the excellent Telemedicine facilities available at SGPGI.

The clinic attendance was deliberately restricted to a few patients per day to allow for more time for teaching.

Overall this model (a short, intensive, course, focussing on one area) seemed to work quite well, with positive feedback.

Below are some pictures from my visit.


SGPGI Campus pictures


Families at Clinic


Teaching Sessions

EMA and FDA aim to alleviate burden of paediatric Gaucher trials

The challenges of designing and conducting clinical trials in children suffering from LSD’s, and the attendant burden on their families, are well known.

The EMA and the FDA have recently jointly published a strategy document on drug development research in paediatric Gaucher disease. The key recommendations are:-

  1. That specific paediatric trials no longer be carried out. Instead, data from adult trials and paediatric populations can be modelled to be applied to paediatric patients.
  2. Safety and efficacy be studied in the same trial.
  3. There may be a case for conducting multi-arm, multi-company trials.

These are important and welcome recommendations which, if formalised, will achieve two important outcomes:-

  1. Reducing the need for affected children to participate in clinical trials (and the attendant burden on their families).
  2. Considerably reducing the time and cost involved.

Although the recommendations apply to Gaucher disease, one can see no reason why it should not be possible to include other LSD’s in due course.

Here is the link to the EMA website from which the document can be downloaded.

Gaucher disease: a strategic collaborative approach from the European Medicines Agency and Food and Drug Administration


MPS II: Analysis of the mouse brain throws new light on some aspects of neurological involvement.

Mucopolysaccharidosis type II is often associated with challenging, disruptive behaviour and varying rates of cognitive decline. However, the underlying mechanisms are only poorly understood.

Now, several teams from Padova, Italy, have published findings that shed new light on this area. They performed an analysis of the MPS II mouse brain, using RNA sequencing (RNA-Seq). A detailed description is beyond the scope of this post, but basically RNA-Seq is an example of next generation sequencing that is widely used to study gene expression by transcriptome profiling. The transcriptome is the complete set of transcripts in a cell, and their quantity, for a specific developmental stage or physiological condition. Understanding the transcriptome is essential for interpreting the functional elements of the genome and revealing the molecular constituents of cells and tissues, and also for understanding development and disease.

The researchers investigated genes known to be involved in many aspects of neurological function. They found that there was dysregulation of many of these genes, for example calcium homeostasis, axon guidance, mitochondrial function, oxidative stress and circadian rhythm.

Several of these, for example mitochondrial function and oxidative stress, are involved in different stages of the Parkinson Disease pathway. A particularly important finding was the upregulation of alpha-synuclein, the accumulation of which is responsible for synucleopathies such as Parkinson’s disease (PD). For many years, Gaucher disease was the only lysosomal storage disorder (LSD) thought to be associated with PD. However, in recent years such as association has been described in other LSD’s such as Niemann-Pick disease type I and sphingomyelinase deficiency. Accumulation of alpha-synuclein has been demonstrated in the cortex of patients with MPS III. While PD has not yet been described in MPS II patients, it seems that it is only a matter of time before such an association is reported.

Alpha-synuclein also contributes to the development of Alzheimer’s disease. Its accumulation may therefore be of relevance to the cognitive decline that is seen in many MPS II patients.

It is quite possible that patients with MPS II will be found to have similar patterns of gene dysregulation to those seen in the mouse model. Were this to be found to be the case, it may well have implications for counselling and management.

However, a note of caution is required. The MPS II mouse has a single mutation;  whereas human MPS II is caused by many mutations in the IDS gene. So even assuming that similar gene dysregulation to that seen in the mouse will be seen in human MPS II, we dont know how this will be linked to the individual mutations seen in patients. For example, will the gene controlling circadian rhythm be affected more severely in patients with certain MPS II mutations than others?

We also need to bear in mind that, while some aspects of human behaviour may be controlled by the genome, others may well be related to as yet unidentified epigenetic factors. Epigenetics is the term given to the modification of gene expression rather than the genetic code itself. The human epigenome has not yet been fully characterised; work on this is under way.

It may therefore be some time before we have answers to these important questions. Nevertheless, these are important findings that are likely to greatly improve our understanding of the complex neurological and neuropsychiatric features seen in MPS II.