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.