First, we need to understand which mutations lead to a gain of function of the protein (GOF) and which ones to a loss of function (LOF). This is because the therapeutic strategies are opposite: stop the mutated protein for GOF, and increase the healthy one for LOF.
We aim to pursue the following strategies to find treatments:
Target AGO1 and AGO2 proteins: repurposing existing drugs or finding novel small-molecule drugs
Target AGO1 and AGO2 RNA: antisense oligonucleotides to upregulate activity for LOF (splicing) or shut down the mutated protein for GOF
Target AGO1 and AGO2 DNA: gene replacement therapy (LOF only) and gene editing
A better understanding of a) disease mechanisms and b) how the disease presents itself gained from our earlier phases will strongly guide the development of therapeutic approaches.
Learn more on this page about the three approaches and why we believe in them.
As we don't know yet strategy will work best, we will go after these strategies in parallel.
Small molecule drugs to increase or reduce production or activity of AGO1/2, starting with screening already approved or developed drugs for off-target effects
What is it? Most drugs on the market are small molecule drugs. Repurposing an existing drug has the potential to be the fastest and cheapest way to treatment. We aim to screen drugs for off-target effects on AGO2, up- or downstream biological processes in patient-derived model systems.
Can it work? For a rare, genetically-caused rapid-aging disease, a collaboration of scientists, industry and Progeria Research Foundation has successfully brought a repurposed drug to market (FDA, Progeria Research Foundation). Other rare diseases are also close to/in trial with stunning results (PMM2-CDG, SLC6A1).
For gain of function mutations shut down mutated AGO1/2, and for loss of function mutations upregulate production of healthy AGO1/2 with a splicing antisense oligonucleotide (ASO) or regulatory element ASO
What is it? Antisense oligonucleotides (ASOs) are a novel, promising type of drugs targeted to specific gene defects. These drugs either shut down gene expression or correct the reduced level of a functional protein in the body. ASOs are synthetic chains of nucleotides - the material our genes are made of - that bind to complementary target mRNA, which is an intermediate product between gene and protein, thus regulating gene expression (sound familiar?). To shut down gene expression, an ASO is produced that recognizes mutated AGO1/2 mRNA and stops its expression. To upregulate the expression of AGO2 with ASOs, we can either pursue an approach that modulates mRNA splicing, which was recently published by Stoke Therapeutics for other loss-of-function mutations, or an approach that targets regulatory elements.
Can it work? Spinraza, a splice-modifying ASO to treat spinal muscular atrophy (SMA), was approved by the FDA in 2016. Stoke's ASO for Dravet syndrome (which uses the above-mentioned approach) is now in clinical trials, as are knock-out ASOs for e.g. Angelman syndrome. The paper by Stoke Therapeutics already identifies a splicing target for AGO2. With covid vaccines, mRNA therapy in general has come into the spotlight and because it can be customised and targeted to a gene it is extremely promising for rare diseases.
Deliver a functional copy of AGO1/2 (AAV-mediated gene therapy) or correct the mutation (CRISPR base editing). The former only works for loss of function mutations.
What is it? This is a cure. Gene therapy permanently adds a new, functional gene to the body (e.g. adeno-associated virus 9 (AAV9)-mediated gene therapy) or corrects the mutation (CRISPR base editing). You can learn more about the concept of gene therapy at the FDA or in this short video made for spinal muscular atrophy (SMA). This approach represents a permanent fix and is the most difficult approach. Delivery to the brain and avoiding an immune responses to the treatment are amongst the challenges.
Can it work? In a breakthrough the FDA approved a gene therapy for a rare form of inherited blindness in 2017, and Novartis' AAV9-based gene therapy Zolgensma for SMA in 2019. The patient organization SMA played a critical role in its development by funding preclinical research and supporting clinical trials. Another AAV-based gene therapy for Duchenne muscular dystrophy is currently in the last phase of clinical trials. CRISPR-based gene editing is still in its infancy with the first human trials targeting the eye or the liver having just started. To push this field forward, the US National Institute of Health has increased funding for genome editing in humans. The FDA predicts that it will approve 10-20 gene therapies a year by 2025.