Team Creates Algorithm to Allocate Gene Therapy for Patients With Inherited Vision Loss

The development of a successful gene therapy for RPE65-associated inherited retinal disease is a major breakthrough, but it also prompts difficult questions about which patients are good candidates for the therapy.

An interdisciplinary team of ophthalmologists, geneticists, and surgeons has proposed new guidelines to confirm which patients with RPE65-associated inherited retinal disease (IRD) are good candidates for gene therapy.

The proposal, which was published in the Orphanet Journal of Rare Diseases, is intended to help pediatricians and ophthalmologists better diagnose the disease and make more informed treatment decisions.

IRD is a category of diseases caused by genetic mutations. RPE65-associated IRD is caused by biallelic mutations in the RPE65 gene, according to corresponding author Francesco Testa, PhD, of the University of Campania Luigi Vanvitelli, in Italy, and colleagues. Patients with the disorder experience a severe form of rod-cone mediated disease, which can lead to total blindness. The disease begins with night blindness in early childhood and sight continues to decline with age.

The disease was previously considered incurable, but Testa and colleagues said a better understanding of the pathophysiological mechanisms at play has led to new therapeutic possibilities, including gene supplementation therapy.

“Monogenic ocular diseases are good candidates for gene transfer therapy, as the eye has favorable anatomical and immunological characteristics, providing a contained physical space protected by the blood-ocular barrier that is particularly suited for local delivery,” the authors explained, adding that RPE65-associated IRD is a “successful model for the development of ocular gene supplementation therapy applied to monogenic diseases.”

The therapy, voretigene neparvovec (Luxturna), was first approved in the United States in 2017 to treat patients with confirmed RPE65-associated IRD who are experiencing vision loss, provided the patients have confirmed RPE65 biallelic mutations and sufficient viable retinal cells.

Yet, determining which patients are actually eligible has been a challenge, Testa and colleagues said, both because of a lack of shared criteria for eligibility, and due to a lack of a process to determine who gets access to the complex procedure.

Testa and colleagues wanted to develop a clinical pathway algorithm that would make it easier for ophthalmologists and geneticists to correctly identify patients suitable for therapy with voretigene neparvovec. They therefore convened a group of Italian experts to create recommendations related to the clinical and genetic characteristics associated with patient eligibility.

After an extensive literature review, the authors drafted a two-round questionnaire which was then circulated to an external panel of ophthalmologists and geneticists with expertise in IRDs.

The result is a summary algorithm, available in the journal article, which will be developed and expanded with additional detail over time. The investigators outlined a process to get patients to therapy, beginning with clinical diagnosis, which they said can help screen patients and identify those for whom the level of suspicion warrants genetic testing. Pediatric patients ought to be prioritized, they said, in order to take full advantage of the therapy, preserve visual acuity, and improve the patient’s quality of life.

The therapy itself should be given by an experienced vitreoretinal surgeon, the investigators said, in a center that has experience treating IRDs and which has access to a pharmacy capable of handling gene therapies.

Testa and colleagues noted that, at present, there is limited availability of genetic testing, and a long turnaround time associated with clinical practice. Thus, they said, the recommendations they published should be viewed as a framework for optimal care going forward. They said voretigene neparvovec is a highly promising therapy, but its use needs to be carefully planned and considered.

“Although voretigene neparvovec makes available to clinicians a treatment with the potential to prevent blindness and provide a life-long beneficial effect for many patients with RPE65-associated IRD, its safe and effective use requires expertise across a multidisciplinary team that includes ophthalmologists, geneticists, surgeons, and patient support services,” they said.


Sodi A, Banfi S, Testa F, et al. RPE65-associated inherited retinal diseases: consensus recommendations for eligibility to gene therapy. Orphanet J Rare Dis. Published online June 4, 2021. doi:10.1186/s13023-021-01868-4