At least 70% of rare diseases – as many as 7,000 disorders – have genetic underpinnings (OMIM; Orphanet). Of those, more than half are attributed to mutations, or variants, in individual genes (OMIM). The Rarebase Function™ platform takes an innovative approach to broadly impact rare genetic diseases by matching their root cause genes to existing drugs. We can simultaneously apply our platform to many rare diseases with genetically-defined root causes, thereby increasing the efficiency and scale of our approach.
How exactly does Function predict drug candidates that target the underlying biology of single-gene rare diseases? It follows a playbook that is determined by different types of gene variants. The goal of Function – and of the Rarebase precision medicine research approach more broadly – is to “rebalance” the expression of root cause genes that are disrupted by disease-causing variants.
Below, we lay out four ways the Function drug discovery platform addresses common types of variants that cause rare genetic diseases.
A note: Each gene is like a blueprint that provides the instructions to make a specific protein inside a cell. Proteins are like the tiny machines that help cells perform their roles in the body, and each protein has a unique job that is determined by its gene sequence. Proteins are made from genes via expression of an intermediate set of instructions. Disease-causing variants can cause too little or too much protein to be made, or disrupt the way proteins work (in other words, disrupt their function or activity).
Some variants turn down the expression of a gene, meaning that there is not enough of its protein product in cells to enable them to work properly. A common example of this is haploinsufficiency, when one of the two copies of a gene in a patient’s cells is broken or turned off. In this case, the Function platform will identify drugs that increase expression of the remaining functional gene copy.
This scenario is more or less the opposite of the first scenario. Sometimes, variants cause a gene to be turned on too high or at the wrong time and thus too much of its protein product is made in cells. In those cases, reducing the expression of the gene can help restore cellular function.
Sometimes, disease-causing variants occur in both copies of a gene, which can lead to complete (or near-complete) loss of the protein product or its activity. In those cases, there is not a healthy copy of the gene to turn on like there is in haploinsufficiency. If the affected gene has a paralog, which is a closely related gene that has a similar function, then turning up the paralog’s expression could help restore function in the affected cells.
Some types of variants don’t affect the amount of gene expression in cells; rather, they affect how the protein product of the affected gene works. These changes are commonly caused by missense variants. Importantly, proteins must interact with other proteins inside cells to do their jobs. Function takes advantage of these “gene pathways” to identify other genes and their protein products that can be turned up or down to rebalance the dysfunction of the root cause gene.
There are approximately 3,700 rare disease root cause genes that may be rebalanced using the approaches described above, and the Function platform is designed to identify potential drug candidates for each of these genes. Rarebase provides an innovative opportunity to more efficiently discover potential solutions for people living with rare genetic diseases.
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