OFF-TARGET RESOURCE CORE

PROJECT SUMMARY Off-target editing analyses will be so fundamental to the development of our therapeutic leads, regardless of the disease treated—whether phenylketonuria (Lead Project 1), hereditary tyrosinemia type 1 (Project 2), or mucopolysaccharidosis type I (Project 3)—and so integral to any IND applications that ultimately emerge from the Projects, that we are proposing an Off-Target Resource Core that will serve all three Research Projects. This Resource Core will provide services that are directly aligned with the preclinical studies that are recommended by the U.S. Food and Drug Administration (FDA) Draft Guidance for Industry on Human Gene Therapy Products Incorporating Human Genome Editing, namely: (1) identification of on-target and off-target editing activity, including the type, frequency, and location of all off-target editing events, taking into account human genetic variation; (2) assessment of genomic integrity, including chromosomal rearrangements, large insertions, or large deletions; and (3) evaluation of the biological consequences associated with off-target editing.