UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Messenger RNA therapy for neuronopathic Gaucher disease

Supervisors names
Julien Baruteau 
Sonam Gurung

Gaucher disease (GD), one of the most common lysosomal storage diseases, is caused by glucocerebrosidase deficiency. This leads to damaging accumulation of specific glycolipids in various organs, which generates a clinical spectrum of disease severity. Although >90% of patients will only present with a visceral disease (GD 1), a small subset of patients will present a neurodegenerative disease or neuronopathic GD (nGD), either with an acute deterioration and early death in infancy (GD2) or a chronic and progressively worsening neurological disease (GD3). The incidence of the disease is 5 and 0.5 patients/100,000 live births for GD and nGD, respectively. 

The standard of care for GD relies on recombinant enzyme replacement therapy or substrate reduction therapy to reduce the toxic accumulation of glycolipids. This improves most of the symptoms of the visceral disease but these therapies have no effect on the neurological disease. Therefore GD2 and GD3 patients, who do not have any disease-modifying therapy to treat their neurodegenerative disease, are the GD patients with the most unmet needs. 
Messenger RNA (mRNA) replacement therapy is a novel gene therapy technology, which is rapidly reaching maturity and has shown its potent efficacy and high safety profile during the recent COVID-19 pandemic. mRNA therapy is actively being developed in many areas including rare genetic diseases and is currently in clinical trials for various paediatric liver inherited metabolic diseases with promising outcomes. 

In this proposal, the applicant will build upon our in-house lipid nanoparticle (LNP) system, enabling diffuse and homogeneous cerebral biodistribution. He will develop mRNA therapy for nGD. He will engineer the mRNA and lipid nanoparticle (LNP) design to maximise efficacy. He will then test our lead construct in a mouse model, which recapitulates the human phenotype of nGD. He will assess cerebral biodistribution via different modalities of administration and identify a minimal effective dose. With this approach, we ultimately aim to treat both the neurological and the visceral diseases with the same mRNA-LNP construct with combined intracerebral and systemic administrations respectively. The applicant will accelerate clinical translation by studying large-scale manufacturing and engaging with patients’ association. 

mRNA-LNP has a transformative potential for cerebral monogenic diseases. The aim is to develop mRNA encapsulated in lipid nanoparticles (LNP) to treat the chronic form of nGD i.e. GD3. 

The objectives are

  • Objective 1: Optimisation of mRNA and LNP design
  • Objective 2: Proof of concept in vivo in nGD mice
  • Objective 3: Clinical trial readiness: Microfluidic scalable production and engagement with Gaucher patients’association 

Objective 1: Molecular biology, cloning, cell culture, mRNA-LNP production and characterisation
Objective 2: Proof of concept in vivo: animal work, immunostaining, enzyme tests, mass spectrometry
Objective 3: Microfluidic systems

OBJECTIVE 1: (Months 1-12): 
OBJECTIVE 2. Proof of concept in vivo (Months 13-30)
OBJECTIVE 3. Clinical trial readiness (Months 18-30)
THESIS WRITING (Months 30-36)

1. D’Amore et al.2021, PMID 34649574. 
2. Enquist et al.2007, PMID 17954912. 
*3. Massaro et al. 2018, PMID 30013199. 
*4. Grant-Serroukh et al.2022, PMID 35718210. 
*5. Gurung et al.2022, BioRxiv https://biorxiv.org/cgi/content/short/2022.10.19.512931v1. 

Julien Baruteau, j.baruteau@ucl.ac.uk