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I would also like to start this section thanking all the researchers, doctors and health care professionals that work together in order to discover and apply new treatments and therapies which benefit the most vulnerable patients.

Among them, we can luckily mention several outstanding professionals:  Doctor Derks, Dr Maaike Oosterveer, Dr Brunetti-Pierri, Doctor Weinstein, Profesor Youngmok Lee, Doctor Grünert, Doctor Wortmann, Dr Janice Chou, Dr Matarese, Dr Trepiccione, Profesor Veiga-da-Cunha, Profesor Schaftingen …etc.

GENE THERAPY

One of the main research projects is the “gene therapy”. In my case, the initial idea a few years ago was to do in vivo somatic gene therapy to treat the glucose problem and ex vivo to treat neutropenia.

No worries! I will also explain this with baby words 🙂

As I mentioned before, I have a mutation in one of my genes so my liver is not getting the right information to work properly and it is not breaking glycogen down into glucose. The idea is to put inside my body (in vivo) the right version of my mutated gene.

This gene is introduced in a virus which viral component has previously been removed. The virus is inserted into my liver to leave the right gene inside. This gene modifies certain liver cells so that they start working properly. This is how my body will be able to produce glucose and avoid hypoglycemia.

This is not called a cure but a therapy. It will not cure me for good but it will make my body work properly for (hopefully) months or years. After some time I may need some kind of “reminders”. 

This therapy has been tested in mice and dogs for several years. Watch the following video in which Dr. W explains the gene therapy and you will see how these animals suffering GSD and having severe hypoglycemia are treated with the right genes. Not only they quickly get better but they also manage to maintain this improvement for long time. The levels of glucose in blood remain stable and the storage of glycogen decreases. Overall, all indicators improve.

All this would help me a lot and would also be useful as a model to cure other liver diseases. Currently, clinical trials in humans are being carried out for GSD 1a in several countries (USA, Spain, The Netherlands….etc). We hope all will go well and that the gene therapy can also be developed for GSD 1b. This will require further research so more funds are needed.

In my case, even if the liver problem was solved, I would still need to deal with the neutropenia. For this challenge we cannot use the same approach because the problem is not in the liver but in the bone marrow. The virus used to introduce the right gene in the liver cannot be used for the bone marrow.

This is why, initially, ex vivo gene therapy was considered. The method consists on extracting the bone marrow’s stem cells and once outside the body they go through gene therapy. Some of these stem cells are modified and start working properly. They are reproduced to get millions of them and they are reinserted in the bone marrow which becomes more functional and results on a stronger immune system.

As reasearch advances and other therapies and treatments come up, there might be different possibilities to combine gene therapy for the liver with a different treatment for neutropenia, for instance. 

TREATING NEUTROPENIA AND NEUTROPHIL DYSFUNCTION WITH AN SGLT2 INHIBITOR

Another very important line of research and treatment is the repurposing of a drug called “empagliflozin” for GSD 1b patients.

The treatment is based on a research publication (Veiga-da-Cunha et al –PMID: 30626647). In GSD 1b patients, with G6PC3 or G6PT deficiency, the accumulation of 1,5AG6P inhibits glycolysis, something which affect negatively neutrophils since their energy metabolism depends upon it. Therefore, the research suggests that increasing the renal excretion of 1.5AG could be an alternative or complementary treatment of neutropenia in GSD 1b patients. This renal excretion is facilitated by an existing drug called empagliflozin which is normally used for diabetes type II and the use for GSD 1b is a very good example of drug repurposing.

Other articles have been published since then by Doctor Derks and other wonderful Doctors which abstracts you can find through these links: Wartmann et al and Grünert et al

Even a GSD family had the wonderful idea and creativity to make this explanatory video.

As most of you know, I was one of the first persons in the world to follow this off-label treatment at the UMCG in Groningen in September 2019.

Since then, we have written an article in the Journal of Inherited Metabolic Disease, we have published podcast in the University Medical College of Groningen’s area of research, we have participated as panelists in several webinars, conferences, University lectures, together with our dearest Doctor Derks, not only about the off-label treatment with empa but also about the set-up of an internet platform www.emergencyprotocol.net  which generates tailored emergency letters for some metabolic diseases’ patients, including GSD.

mRNA-based THERAPY 

I would also like to talk to you about messenger RNA (mRNA) therapies which are a new revolution to treat rare diseases and which have also been used to create COVID19 vaccines.

The mARN transports a copy of the genetic instructions from genes in the cell nucleus to an outside part call ribosome where these instructions are used to create proteins.

With mARN replacement therapy for GSD1b, the patient’s body would get the right genetic instructions so it would not produce faulty proteins and they would not be affected by the genetic mutation I have.

Having the right version of the proteins would make my body, my liver, maybe even my bone marrow, work well, and most of my problems could be solved. I would need to get several dosis of mARN every now and then but I am sure that it would be extremly worth it.

The good thing with mRNA-based therapy is that it is easier to implement and to adapt to each patient, allowing for a more personalized treatment. In addition, it is delivered through lipids nanoparticles (not via virus as the gene therapy) so there is no issue with potential antibodies the patient may have.

Currently there is an ongoing project mRNA replacement therapy for GSD1b lead by Dr. Brunetti-Pierri within the Telethon Foundation in Italy. I am very happy that this initiative is ongoing and I will be following it up very closely.

These documents explain very well how mRNA therapies work in general: mRNA therapy for rare diseases (video) y Using synthetic biology to craft one time programmable mrna therapeutics (podcast).

GENE EDITING

Gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism.

This kind of research is still at an early stage and there is a lot to discover. Howeverm there are chances that it could actully become a long term treatment or solution if it works properly.

Some results have already been achieved for GSD 1a which are described in this article by Maaike Oosterveer et al and  this other by Janice Y. Chou et al.

Other ongoing research projects deal with: