ARID1B-related disorders: novel therapies and mechanist insights.
Lead Research Organisation:
UNIVERSITY COLLEGE LONDON
Department Name: Neuroscience Physiology and Pharmacology
Abstract
AT-Rich Interaction Domain 1B (ARID1B or BAF250B) is a gene that encodes for the ARID1B protein, which is a functional component of the multi-subunit SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, and its mammalian homologue, BRG1/BRM associated factor (BAF) complex. These complexes modify chromatin in an ATP dependent fashion and are crucial for regulating gene expression and differentiation.
Over recent years, exome sequencing studies have showed some people with neurodevelopmental disorders have de novo heterozygous truncating mutations in
ARID1B results in a haploinsufficiency, this disorder is termed ARID1B-related disorder (ARID1B-RD). A wide range of phenotypes arise in patients with ARID1B-RD, it was initially associated with intellectual disabilities (ID), with the first patient with a phenotype likely associated with ARID1B reported in 1998. Further reports published patients with ARID1B truncations, presenting epileptic seizures, hearing loss, delayed brain development and autism spectrum disorders (ASDs). There has also been recent interest in the cancer field. ARID1B is thought to act as a tumour suppressor however ARID1B mutations are implicated in driving tumour aggression and found to be frequently co-mutated in ARID1A cancers.
Patients with ARID1B haploinsufficiency are prime candidates for gene therapy (GT) and published Arid1b+/- mouse models exhibit behavioural and cellular defects similar to those with ARID1B-RD. Patients treated with GTs are injected with a viral vector carrying genetic machinery to either make DNA changes or upregulate or downregulate the gene of interest.
The first aim for my project is to trial and test a GT to increase Arid1b in mouse and human models. We will first test the therapy in rodents with the aim of rescuing the Arid1b+/- phenotype seen in published models. This will initially be tested at the cellular level in terms of protein and gene expression, then we will investigate the impact our GT has on Arid1b+/- mouse behaviour.
The cellular and molecular basis which drive symptoms in ARID1B-RD is not fully understood. During development, neuronal circuits are formed and refined during critical periods, sculpted by robust genetic and epigenetic programmes in a cell specific manner. We have seen Arid1b+/- is responsible for perturbed development but the extent of the mechanisms is unclear. The second aim of my project will be to explore how therapeutic intervention at different stages of development can rescue Arid1b+/- phenotypes.
This work will contribute to our understanding of neurodevelopmental
disorders in patients with ARID1B mutations, whilst providing a potential life-changing
therapy for future ARID1B-RD patients.
Over recent years, exome sequencing studies have showed some people with neurodevelopmental disorders have de novo heterozygous truncating mutations in
ARID1B results in a haploinsufficiency, this disorder is termed ARID1B-related disorder (ARID1B-RD). A wide range of phenotypes arise in patients with ARID1B-RD, it was initially associated with intellectual disabilities (ID), with the first patient with a phenotype likely associated with ARID1B reported in 1998. Further reports published patients with ARID1B truncations, presenting epileptic seizures, hearing loss, delayed brain development and autism spectrum disorders (ASDs). There has also been recent interest in the cancer field. ARID1B is thought to act as a tumour suppressor however ARID1B mutations are implicated in driving tumour aggression and found to be frequently co-mutated in ARID1A cancers.
Patients with ARID1B haploinsufficiency are prime candidates for gene therapy (GT) and published Arid1b+/- mouse models exhibit behavioural and cellular defects similar to those with ARID1B-RD. Patients treated with GTs are injected with a viral vector carrying genetic machinery to either make DNA changes or upregulate or downregulate the gene of interest.
The first aim for my project is to trial and test a GT to increase Arid1b in mouse and human models. We will first test the therapy in rodents with the aim of rescuing the Arid1b+/- phenotype seen in published models. This will initially be tested at the cellular level in terms of protein and gene expression, then we will investigate the impact our GT has on Arid1b+/- mouse behaviour.
The cellular and molecular basis which drive symptoms in ARID1B-RD is not fully understood. During development, neuronal circuits are formed and refined during critical periods, sculpted by robust genetic and epigenetic programmes in a cell specific manner. We have seen Arid1b+/- is responsible for perturbed development but the extent of the mechanisms is unclear. The second aim of my project will be to explore how therapeutic intervention at different stages of development can rescue Arid1b+/- phenotypes.
This work will contribute to our understanding of neurodevelopmental
disorders in patients with ARID1B mutations, whilst providing a potential life-changing
therapy for future ARID1B-RD patients.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/W006774/1 | 30/09/2022 | 29/09/2028 | |||
| 2720584 | Studentship | MR/W006774/1 | 30/09/2022 | 29/09/2026 |