2017: First Gene Therapy Approved (Luxturna) (2017)

The FDA approval of voretigene neparvovec (Luxturna, Spark Therapeutics) in December 2017 for
RPE65 mutation-associated retinal dystrophy became the first in vivo gene therapy approved in the
United States for a genetic disease and only the second gene therapy approval globally. The drug
delivers a functional copy of the RPE65 gene—encoding retinal pigment epithelium 65 kDa protein,
essential for the visual cycle—using an adeno-associated virus serotype 2 (AAV2) vector administered
by subretinal injection beneath the macular photoreceptors.

RPE65-associated Leber congenital amaurosis and retinitis pigmentosa cause severe visual
impairment from infancy and progress to complete blindness; no treatments had existed before
Luxturna. The pivotal trial enrolled patients with confirmed RPE65 biallelic mutations and
measured improvement on a functional multi-luminance mobility test—a standardised obstacle course
navigated at multiple light levels. Treated patients showed significant and clinically meaningful
improvements in light sensitivity and navigational ability that were maintained at follow-up visits
extending to three or more years.

Albert Maguire and Jean Bennett at the University of Pennsylvania led the clinical development,
building on decades of foundational work characterising the visual cycle biochemistry. The drug
was approved at a price of $850,000 ($425,000 per eye), triggering extensive debate about one-time
cure pricing models and rebate structures; Spark partnered with payers on outcomes-based agreements
in which payment was contingent on sustained visual improvement at 30 and 90 days post-treatment.

Luxturna's approval validated AAV-mediated in vivo gene delivery as a safe and effective
therapeutic platform, providing a regulatory and manufacturing template for subsequent gene
therapies across neuromuscular, haematological, and metabolic diseases.