Safety and efficacy of perinatal gene therapy for Neuronopathic Gaucher disease

Lead Research Organisation: University College London
Department Name: Maternal & Fetal Medicine


Gaucher disease is a genetic disease which, in its severe form, results in serious brain damage infant death before two years of age. The disease is incurable with currently-available drugs since they can?t enter the nerves in the brain. Gene therapy has already been used to cure several genetic diseases and, very recently, it has become possible to deliver genes to the brain. Based on this recent finding, we are trying to cure a mouse model of the human brain disease using gene therapy. We will be injecting the gene into bloodstream of fetal and neonatal mice to see if this prevents the onset of brain disease. If this works it may provide a pathway towards treating human beings; at the very least we will learn more about why the disease damages the brain in infants.

Technical Summary

Neuronopathic (Type II) Gaucher disease is fatal neurodegenerative disease of infancy caused by deficiency of the enzyme Glucocerebrosidase. Unlike the less severe forms of the disease (Types I and III) which are partially treatable by enzyme replacement therapy, neuronopathic gaucher disease is untreatable since intravenous injection of enzyme does not allow uptake by neurons of the central nervous system. Moreover, neuronal pathology is already present in utero.
A glucocerebrosidase-deficient mouse model of the disease accurately reflects its neonatal lethality likely arising from early motor neuron death. Reconstitution of the enzyme defect in microglia is insufficient to prevent early demise. It is suspected but, as yet, unproven that neuronal glucocerebrosidase expression is essential for prevention of neurological damage. Since pathological changes can already be detected before birth it is possible that even neonatal intervention would be inadequate.
My laboratory specialises in the study of fetal or early neonatal gene transfer for monogenetic disorders. Recently we have observed that administration of adeno-associated virus pseudotype 2/9 to deliver GFP cDNA to neonatal and fetal mice results in very extensive transduction of the central and peripheral nervous system. We have also shown that gene transfer to patient cells can correct the metabolic dysregulation.
In this grant we propose to deliver an AAV2/9 vector by intravenous injection to the mouse model of neuronopathic Gaucher disease in utero (at 15 days gestation, birth at 20 days) and in D0/1 neonates. We aim to test the hypothesis that early reconstitution of neuronal expression of glucocerebrosidase is sufficient to prevent the early demise in these mice. This study would also aim to differentiate the efficacy of fetal and neonatal intervention.
From Professor Stefan Karlsson (Lund, Sweden) we have acquired a breeding colony of glucocerebrosidase-deficient mice the homozygotes of which display a clear phenotype of early neurological damage and demise.


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Buckinx R (2016) Proof-of-concept: neonatal intravenous injection of adeno-associated virus vectors results in successful transduction of myenteric and submucosal neurons in the mouse small and large intestine. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Karda R (2014) Perinatal systemic gene delivery using adeno-associated viral vectors. in Frontiers in molecular neuroscience

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Mattar CN (2015) Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Title Pathology of GBA knockout mice 
Description We have characterised inflammation occurring early in the knockout GBA mouse model 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact Too early as yet 
Description 5th Neuronopathic Gaucher Disease Family Conference, Reading Hilton, 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Patients, their families and other stakeholders attended this meeting hosted by the Gauchers Assocation Limited. The presentations stimulated many questions from the attendees afterwards

Nothing specific, to date
Year(s) Of Engagement Activity 2011
Description Presentation at the British Society for Gene Therapy/European Society of Gene and Cell Therapy Public Engagement Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Around 200 6th formers/lay public attended, stimulating many questions from the presenter

The radio presenter from Radio East Anglia expressed an interest in visiting our laboratory
Year(s) Of Engagement Activity 2011
Description Talk at the British Society for Gene and Cell Therapy Public Engagement Day, March 2019, Natural History Museum, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The British Society of Gene & Cell Therapy runs annual public engagement days where schools and public are invited to hear talks by researchers in the area of gene and cell therapy. There are also lunchtime activities around genetics, gene and cell therapy. After each talk, school children are often forthcoming with questions.
Year(s) Of Engagement Activity 2019