Protein misfolding in hemophilia.

Over the past century, the development of advancements in hemophilia therapy has experienced unprecedented success, starting with virally contaminated blood product infusions and progressing to safe plasma-derived and recombinant factor replacements, non-factor based rebalancing agents, long-lasting gene therapies, and moving forward into an era of potentially curative gene editing. Hemophilia A (FVIII deficiency) and B (FIX deficiency) are rare, monogenic, congenital bleeding disorders caused by mutations in the F8 and F9 genes, respectively. These mutations, along with environmental and cellular stressors, result in the translation of misfolded FVIII or FIX proteins, leaving patients with hemophilia susceptible to spontaneous bleeding and hemophilic arthropathy. Misfolded FVIII or FIX proteins show reduced clotting activity, are more vulnerable to degradation, and contribute to cellular stress and immune activation. Hemophilia is diagnosed using a combination of functional and immunological assays to detect Factor VIII or FIX activity and protein levels, which are proportional to phenotype severity. Newer approaches to clinical management of hemophilia include intravenous half-life extended clotting factor preparations, subcutaneous non-factor treatments and three gene therapies approved by the U.S. Food and Drug Administration. Gene therapy provides longer-term, therapeutic factor levels without the need for clotting factor replacement prophylaxis. Ongoing research to further improve therapeutic options is focused on small molecule therapies such as molecular chaperones and protein stabilizers, as well as CRISPR/Cas9 gene editing tools with curative potential. In combination with innovative therapeutic strategies, it will remain critical to bolster patient adherence to treatments by advocating for patients to play an active role in making decisions about their health care.