In light of the recent statement
made by US Food and Drug Administration (FDA)’s Commissioner, Scott Gottlieb, MD, regarding the new guidance documents for gene therapy development, the rare disease community is buzzing. Researchers working with rare diseases that have genetic origins are increasingly turning to the use of these therapies as potential treatment options. With over 7,000 rare diseases existing and more being detected every year, the growing need for effective treatment options is underscored.
In a laboratory at Children's Hospital of Orange County (CHOC) Children’s Research Institute, researchers are working on
developing personalized CRISPR-Cas9 genome editing therapeutics for rare diseases, with a specific focus on the progressive cardiac and skeletal myopathy lysosomal storage disorder (LSD), Pompe disease. Research scientist, Jeffrey Huang, PhD, is helping lead the way.
“Over 30 million Americans—nearly 1 in 10 people
—suffer from 1 of the 7,000 conditions classified as a rare disease,” said Dr Huang in a recent interview
. “Many rare disorders often lead to progressively debilitating and sometimes fatal outcomes in infants and children. Unfortunately, there are no cures for most rare diseases; if existent, current therapy only attenuates or slows disease progression. My primary research focus is to evaluate and develop CRISPR genome editing therapeutics to address deficiencies of existing treatment for rare pediatric disorders, such as Pompe disease.”
Aside from evaluating the safety and efficacy of the CRISPR genome editing, Dr Huang also hopes to accomplish the following with his research project: generate animal models of Pompe disease that bear mutations homologous to those that cause human Pompe disease, fully assess and validate the animal models generated to ensure molecular, biochemical, histopathological and functional analogy to human Pompe disease, and develop CRISPR genome editing/delivery systems that would correct mutations in validated models of Pompe disease.
Huang feels confident that he can prove CRISPR genome editing is superior to recombinant GAA enzyme (rhGAA) replacement therapy.
While rhGAA was approved by the FDA in 2006 for its effectiveness at getting rid of glycogen in heart muscle and reversing heart symptoms in those with Pompe disease; however, surviving children still experience glycogen buildup in other muscles and continue to struggle with basic activities such as talking, walking, eating, or breathing. Additionally, outcomes of infantile-onset Pompe disease vary according to cross-reactive immunologic material (CRIM) status, which is an individual’s own immunogenic response to rhGAA.
As such, the need for a more effective and personalized Pompe disease therapeutic has become clear, and CRISPR genome editing may be able to fill that need. Dr Huang and his team set out to create and characterize new models of Pompe disease with single nucleotide GAA mutations commonly found in human patients. Through the use of CRISPR genome editing, they were able to successfully introduce 2 infantile-onset Pompe disease knock-in mutations into cultured mouse myoblasts and transgenic mice: GAA c.1826insA (CRIM-) and GAA c.1935C>A (CRIM+). Using whole-genome sequencing, they were able to confirm on-target editing specificity and screen for potential off-targets.
“I am excited to report that within the past year we have successfully demonstrated that our Pompe disease-specific CRISPR genome editing strategy has produced the desired mutations in cultured cells,” added Dr Huang. “We are currently expanding this new animal model of Pompe disease and will perform the appropriate tests on the expanded cohort to confirm analogy to human Pompe disease. Our newly generated Pompe animal models will form the basis for future studies that will test the efficacy and safety of CRISPR-mediated genome correction in an in vivo context.”