Oral Presentation International Congress on Neuronal Ceroid Lipofuscinoses 2025

An mRNA Gene Therapy Platform for Childhood Dementia: Initial findings with Niemann-Pick C and ongoing challenges (127748)

Ya Hui Hung 1 2 , Mahi Mhatre 1 2 , Yuwei Zhang 1 2 , Tianxia Zhang 3 , Colin Pouton 3 , Mark Walterfang 2 4 , Ashley I. Bush 1 2
  1. The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
  2. The University of Melbourne, Parkville, 3052, Australia
  3. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  4. Neupsychiatry Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia

Childhood dementia encompasses over 100 neurodegenerative genetic disorders that lead to progressive cognitive decline and loss of function in affected children. Niemann-Pick Disease Type C1 (NP-C1) serves as a lead indication for mRNA gene therapy, exemplifying the potential of this innovative approach to address the underlying genetic causes of such conditions. NP-C1 is characterised by mutations in the NPC1 gene, resulting in impaired cholesterol transport and subsequent neurodegeneration.

Messenger RNA (mRNA) gene therapy has gained significant attention, particularly following the success of COVID-19 mRNA vaccines. This strategy allows for the direct delivery of therapeutic mRNA, which can produce functional proteins within target cells, potentially reversing the effects of genetic mutations. Unlike traditional gene therapies, mRNA does not integrate into the host genome, minimising the risk of insertional mutagenesis.

Our research focuses on developing a versatile mRNA gene therapy platform, using NP-C1 as a primary model. We have demonstrated the efficacy of therapeutic mRNA in pre-clinical models, successfully restoring NPC1 protein expression and alleviating the toxic effects of lipid accumulation. This platform not only addresses NP-C1 but also has potential transferability to other childhood dementia conditions, such as Batten disease, by targeting the underlying genetic defects.

To enhance the stability and delivery of mRNA, we are exploring modified mRNA formulations and lipid nanoparticle carriers. These advancements aim to improve the bioavailability of mRNA, particularly in the central nervous system, where effective delivery remains a significant challenge.

By optimising lipid nanoparticle formulations to facilitate crossing the blood-brain barrier, we aim to ensure that therapeutic mRNA reaches its target sites in the brain. Through this mRNA gene therapy platform, we seek to provide new hope for children affected by NP-C1 and other childhood dementia conditions, paving the way for innovative treatments that address the root causes of these debilitating disorders.