Accelerating the development of life-changing treatments for ARID1B-RD
FAR is excited to announce the first stage of a new FAR-funded research project in collaboration with Professor Gabriele Lignani and his team at University College London (UK) to develop and test ARID1B-targeted gene therapy tools for treating ARID1B-RD.
FAR is excited to announce the first stage of a new FAR-funded research project in collaboration with Professor Gabriele Lignani and his team at University College London (UK).
In this project, Prof. Lignani and his team, led by Dr. Jenna Carpenter, will develop and test ARID1B-targeted gene therapy tools for treating ARID1B-RD. These tools, if successful, could be relevant to all types of ARID1B pathogenic variants. In the first phase of the project, taking place over the next 12 months, the Lignani lab will develop the tools and evaluate their potential in human and mouse neurons. If there are positive results, the next phase of the project will involve evaluation of these tools in more sophisticated models, that is, in ARID1B-RD brain organoids and mouse model.
This research project complements FAR’s ASO project. While ASOs target RNA, the gene therapy tools that will be developed by Prof. Lignani target the DNA itself. This distinction has critical implications – successful gene therapy requires single dosing and has long-term effects (unlike ASOs, whose effects are temporal). The approach taken by Prof. Lignani has shown great promise in models of other comparable neurodevelopmental disorders (inc. Dravet syndrome and SCN2A-RD).Prof. Lignani is internationally recognized for his achievements in developing gene therapy approaches for rare genetic brain disorders (particularly the intractable epilepsy Dravet syndrome). He has recently been awarded the prestigious Michael Prize for the best scientific contribution to experimental epilepsy research!
We all hold great hopes for this project and are looking forward to hearing about the preliminary findings.
FAR has initiated an exciting collaboration between Mahzi Therapeutics, a biotech company specializing in genetic therapies for rare genetic neurodevelopmental disorders, Dr. Gijs Santen (Leiden University Medical Center), and Prof. Frank Jacobs (University of Amsterdam) to test an ASO-based potential therapeutic for ARID1B-RD. ARID1B-RD is caused by haploinsufficiency. It means that only one of the two alleles (i.e., gene copies) that code for the ARID1B protein is not functional. Because the other allele functions normally it can be potentially regulated to increase its protein production to a typical cellular level. This up-regulation is the objective of the investigational ASO Mahzi is researching.
ASOs, or antisense oligonucleotides, are synthetic molecules that can attach themselves to RNA strands (‘working copies’ of the gene that serves as a basis for protein production) and affect their function. Mahzi’s ASO is designed to increase the expression of the functional ARID1B allele, an approach that, if successful, could be relevant to all types of ARID1B pathogenic variants.
The rationale for starting the search for ASO-based therapies is three-fold:
1. ASO therapy is an established therapeutic modality, with several ASO molecules approved in the US and the EU for different genetic disorders, and many more are currently in trials.
2. There are scientifically proven methods to deliver ASOs to the brain.
3. ASOs do not attach themselves to the DNA, cannot change it, and thus their effect is only temporal (i.e., two to three months), and thus, reversible.
In this collaborative project, Dr. Santen and Prof. Jacobs will first examine the impact of Mahzi’sASO on cells derived from individuals with ARID1B-RD (12-month timeline). If the cells react as expected, we will proceed with testing the ASO on ARID1B-RD brain organoids and mice.
This is the first time an investigational genetic treatment for ARID1B-RD is being developed and tested. Looking sideways, the therapeutic effects of ASOs for comparable monogenic neurodevelopmental disorders (i.e., Angelman syndrome, Dravet syndrome, Rett Syndrome) are already being evaluated in clinical trials with children. Initial results should be published soon, and we are deeply hopeful that they will be positive. Looking forward, while keeping in mind that there are no guarantees, we believe our children will be able to benefit from such research and potential treatments.