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Gene Therapy

June 2015

The first step to Gene Therapy for Gaucher Disease …….

 The UK Gauchers Association is delighted to announce that on 12 February 2015 the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA) granted a positive opinion for orphan designation (EMA/OD/303/14) to the Association (as the sponsor) for adeno-associated viral vector serotype 9 containing the human glucocerebrosidase gene (Gene Therapy) as a new potential treatment for Gaucher disease.

The regulatory world in Europe can seem overwhelming, as it requires navigating between the National Competent Authority (NCA) in each Member State and the European Medicines Agency (EMA).

To benefit from the EU Regulation on orphan medicinal products for rare diseases, it is necessary to follow a centralised procedure at the EMA. This allows for the designation of orphan medicinal products and puts in place incentives for the research, marketing and development of orphan medicinal products.

Traditionally it has been considered that only pharmaceutical companies can engage in this procedure with the regulators, however this is actually open to individuals and academic / clinical institutions and patient groups.

Tanya Collin-Histed, Chief Executive of the Gauchers Association, said "Whilst existing enzyme replacement and substrate reduction therapies are effective in treating many areas of Gaucher Disease there remain significant unmet needs and challenges. No treatment is available to treat the neurological aspects of the disease which can range from eye movement and auditory processing to myoclonic seizure and premature death. Gene therapy could potentially address this by providing a cure for Gaucher disease. Although this is a first step in the long and complex process of bringing a treatment to market, we are extremely excited to receive this opinion, and to initiate the procedures that allows for communicating directly with the regulators.”

What is Gene Therapy, how does it work and what does it mean potentially for Patients with Gaucher Disease?

Nearly every cell in our body contains a nucleus, each containing an entire, identical blueprint of our entire body. This blueprint is encoded into long strings of DNA which are bundled up tightly into chromosomes, so that they fit in the nucleus. The DNA code is subdivided into genes – each containing the code for an individual protein. Every cell contains the same number of genes (about 24,000) but actually contains duplicate copies of each gene – one from our father, and one from our mother. When we inherit these genes, sometimes from our parents, sometimes the gene copying process introduces an error (a “mutation”) which is so serious that the gene now codes for a protein that can’t function. In many cases this is ok – the copy from our other parent allows us to make sufficient amounts of that protein. However, sometimes if we inherit broken copies from both parents, no functional protein can be made. This is what happens with neuronopathic Gaucher Disease; the patient has inherited two broken copies of the gene encoding Glucocerebrosidase.

The most elegant solution would be to repair the mutation in one or even both copies in every cell in the body. The technology to achieve such efficiency is still in its infancy. However it may be sufficient if we are able to deliver working copies of the genes to a proportion of the right cells. The state of the art tools with which we can achieve this are the basis of a whole field of technology known as gene therapy – delivering genetic material to cure diseases. Nature has provided us with an excellent vehicle to deliver genetic material – the virus. It has been possible to take viruses which infect humans but do no harm, and create synthetic versions (known as “vectors”) which are designed only to deliver working copies of genes.

We have been working to develop a gene therapy treatment for neuronopathic Gaucher Disease. To do this, we have been using a mouse model of this disease, created by Professor Stefan Karlsson in Sweden; affected mice perish before 15 days of age. We injected a vector, known as AAV9, to deliver working copies of the human glucocerebrosidase gene to neurons in the brain of these mice on their day of birth. Most of the treated mice lived more than ten times longer than expected, and were healthy enough to breed. Given the encouraging results with mice, we are now looking at how this treatment might be given to babies diagnosed with this disease.

A session will be held at the nGD family conference on Sunday 15th November to update patients and families on this exciting development, the session will enable families to meet with the researchers and ask questions.

We will keep you updated on our progress as we take each step forward on this long and exciting road by posting updates on our website and Facebook page and in future editions of Gauchers News. 

December 2014

Enzyme Replacement Therapy (ERT) has revolutionised the treatment of patients with Type I Gaucher disease (GD) however Types II and III that affect the brain remain a significant challenge with conventional medicine offering no route to therapy. There is clearly an overwhelming need to develop a treatment.

Drs. Simon Waddington and Ahad Rahim of University College London (UCL) have been developing gene therapy to treat a mouse model that mimics the devastating brain pathology associated to aggressive Type II GD. They have been using viruses that are genetically engineered to remove the ‘bad bits’, rendering them safe, and replacing them with a fully functional and therapeutic glucocerebrosidase (GBA) gene. These viral vectors were injected into the brains of pre-natal or new-born mice where they deliver the therapeutic GBA gene into the cells. A significant increase in the lifespan of the mice was observed together with an amelioration of brain pathology and subsequent improvements in behavioural studies and biochemical markers. This is highly encouraging given the severity of the mouse model – one of the most challenging among neurodegenerative lysosomal storage disorders – and the study is now being prepared for publication.

On the basis of this work, the Gauchers Association and UCL have co-funded an exciting PhD studentship to begin investigating the viral vector administered to the mice via a minimally invasive intravenous route with two fundamental questions requiring answers:

Is this minimally invasive route of administration as effective in extending the lifespan of these mice and is the brain rescued from the lethal neurodegeneration? Intriguingly, given the systemic nature of delivery, does this also address the visceral symptoms?

The PhD studentship was awarded to Miss Giulia Massaro, who recently joined Dr. Rahim’s laboratory and will be working in close collaboration with Dr. Waddington’s group. Giulia began her scientific training in neuroscience as an undergraduate at the University of Padova and postgraduate studies at the University of Trieste where she studied neurodegenerative disorders. The ascendency of gene therapy over recent years means that this studentship is a timely opportunity to develop this technology further for potential application for GD.