Monogenic diseases are known to be caused by a single gene defect, and encompass a large landscape of diseases from Cystic Fibrosis and Muscular Dystrophy, to the Lysosomal Storage Disorders, familial liver diseases and developmental autism variants. From a drug discovery standpoint, the important connection is that there is a single protein target within the cell known to cause the pathology of the disease. That certainty in the cause of the diseases makes monogenic diseases unusual.
In the early days of the biotechnology industry, Genzyme pioneered the treatment of monogenic diseases with its protein replacement for Gaucher’s disease, a lysosomal storage disorder involving mutation of the GBA gene, which codes for the glucocerebrosidase enzyme. By replacing the defective enzyme (through intravenous infusions), Genzyme was able to develop the first truly effective treatment for Gaucher’s disease.
Genzyme repeated that success in several other monogenic diseases involving lysosomal enzymes (including: Fabry disease, MPS-I, Pompe disease and Hunter Syndrome) and demonstrated the power of treating the known cause of a disease with a known corrector of the defect. The paradigm became clear, if you can correct the defect in a monogenic disease, you can make a drug that can be delivered to the right patient (determined through genetic testing) and those patients will benefit.
We’re following in that tradition by focusing on monogenic diseases. We’re taking a small-molecule approach to restoring the defective protein, and that allows us to treat monogenic diseases that may be difficult to treat with other methods, because small molecules can more readily get into the brain, for example, or can restore the activity of a cytoplasmic protein (something enzyme replacement cannot do).