Sharing Experiences in Lysosomal Storage Disorders
Author: Ashok Vellodi
I have had a lifelong interest in lysosomal storage disorders. Having recently retired I now have time to pursue my passion for teaching and training of young doctors and scientists, and hopefully instil in them the passion for their patients that is so integral to working in this field.
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.
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
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.
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.
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.
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
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 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).
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!!
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.
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.
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.