Identifying Promising Targets to Develop Treatments for Rare Diseases

Developing treatments for rare diseases continues to be difficult and expensive. Only 8% of rare diseases have an FDA-designated drug, but a new paper in Orphanet Journal of Rare Diseases outlines a new pipeline for identifying opportunities to develop therapies for rare diseases that do not have treatments. Specifically, the authors focused on genetic diseases.

Of those FDA-designated drugs, cancer, neurological disorders, and genetic diseases are the most commonly-targeted categories. However, genetic diseases are still underrepresented since more than 60% of known rare diseases are caused by mutations in one gene, also known as Mendelian diseases.

The authors examined the current and anticipated orphan drugs and used the Online Mendelian Inheritance in Man to search for rare disease targets.

The researchers built the pipeline based on the following 3 assumptions:

1. The disease target should be caused by a single gain-of-function mutation
2. The disease should have late or adult onset
3. The primary disease gene product should have a solved crystal structure, which is more desirable for inhibitors

The researchers identified some top targetable diseases both due to gain-of-function mutations and loss-of-function mutations, such as Parkinson disease type 8 and type 4, Huntington disease, hereditary pancreatitis, isolated growth hormone deficiency type III, and lung cancer susceptibility. Most of the gain-of-function disease candidates are neuromuscular diseases, which “is consistent with the fact that neurological disorders are one of the most common disease categories in the current FDA orphan drug list,” the authors wrote.

Furthermore, the authors identified disease genes/proteins that might be able to be treated with current FDA-approved drugs since drug repurposing is an important route for orphan drug development.

“Our pipeline provides a list of potential low-hanging fruit for orphan drug research,” the authors concluded. “Drug development programs that are effective at finding inhibitors could focus on the gain-of-function candidates. Known allosteric modulators could be screened against the loss-of-function candidates to quickly evaluate the opportunities for moving forward.”