Hana A. Mansour, MD
Wills Eye Hospital
On the second day of the 2023 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Dr. Edward N. Pugh Jr. introduced the winner of the Proctor Medal Award: Dr. Eric A. Pierce. Dr. Pierce is the William F. Chatlos Professor of Ophthalmology at Harvard Medical School, director of the Berman-Gund Laboratory for the Study of Retinal Degenerations, and the founding director of the Ocular Genomics Institute at Mass Eye and Ear. Dr. Pierce’s work over the past decades has led to a better understanding of inherited retinal degenerations (IRDs) and the development of genetic therapies for several IRDs.
In the lecture, Dr. Pierce reviewed past accomplishments related to the “cycle of translational medicine” which encompasses studying patients with IRD, developing therapeutic trials, and conducting clinical research. While this has led to many advances and potential therapeutic options, he stated that “there is still a lot of work to be done to bring treatments for our patients.”
Dr. Pierce shared several stories about his career path. The first story he shared was related to genetic testing for a 34-year-old patient with rod-cone degeneration. The patient had reduced vision and nyctalopia since age 5, and had recently been experiencing central vision loss and severe visual field constriction. The patient was sent for gene sequencing. Interestingly, his Genetic Eye Disease (GEDi) testing, which uses next-generation sequencing techniques to sequence exons for known genes causing inherited retinal diseases, did not disclose any known abnormalities.
IRDs are genetically heterogenous Mendelian disorders, with 281 disease genes discovered to date. These genes may be inherited in an autosomal (recessive or dominant) or X-linked fashion. Unfortunately, not all patients can achieve a genetic diagnosis. We typically find mutations in known disease genes in 60% of the patients with IRD, while the other 40%, such as this patient, remain unsolved.
From here stems the question: “What are the genetic causes of disease for patients without coding mutations in known disease genes?” One possibility is that there are new disease genes not discovered yet. Another possibility is that there are elusive mutations in known IRDs genes – non-coding mutations that alter splicing or gene expression – or the presence of structural variations such as copy number variations (large deletions or duplications), inversions or translocations.
Progress in gene discovery for inherited dystrophies have come a long way since the early 1990s. Two candidate genes were known in 1990, whereas 277 genes had been identified by 2021 and 281 genes have been cataloged to date. Dr. Pierce question the reason for this missing genetic causality. Possible reasons include variance in splicing signals that can alter splice sites or cause exon skipping, or there may be deep intronic variants that lead to the inclusion of a cryptic exon. Further studies in the 34-year-old patient revealed a variant of unknown significance (VUS) in the RPGR gene: RPGR c.310+7T>G.
We now know that among the 40% of cases without identifiable gene mutations, 6% are due to deep intronic VUS and 17% are due to peri-exonic VUS. We still do not know how to interpret VUS: are they the answer that would lead us to make a diagnosis or just an incidental finding? Dr. Pierce and his team have been working on developing tools such as high throughput splicing assay (HTSA) that allows functional testing of these variants with the aim of gaining a better understanding of the role of VUS.
The second story Dr. Pierce presented was about understanding disease pathogenesis. He recounted a case of a 9-year-old patient with early onset severe retinal degeneration with vision of 20/1000 OD and counting fingers at 6 feet OS along with nystagmus. Genetic testing revealed two mutations in the NMNAT1 gene: p.V9M and duplication of exons 2-4.
NMNAT1 is required for NAD+ synthesis in the nucleus, and NAD+ is needed for DNA repair. Our genome is constantly at risk for DNA breaking from cellular stresses. As long as NAD+ and poly(ADP-ribose) polymerase 1 (PARP1) are available, DNA repair can function normally and genome homeostasis is maintained. Mutations in NMNAT1 in mice lead to a retina-specific decrease in NAD+ and increase in PAR along with associated photoreceptor cell death and retinal degeneration. No treatment is available for (NMNAT1)-associated retinal degeneration, but NMNAT1 gene therapy is being developed.
The third and last story is related to clinical translation. He discussed the story of a 19-year-old female with severe early onset IRD. Vision was LP bilaterally with nystagmus. The genetic cause of her disease was found to be two mutations in CEP290, including the c.2991+1655A>G (IVS26) mutation which was a good target for gene editing therapy.
Dr. Pierce mentioned that six current clinical trials are using the CRISPR/Cas9 program in vivo, including the BRILLIANCE trial, a phase 1/2 study of EDIT-101 for the treatment of CEP290-associated Leber congenital amaurosis 10. The primary endpoints are safety and tolerability of a single sub-retinal dose of EDIT-101, and change in BCVA, full-field stimulus threshold, visual function navigation and vision-related quality of life.
Fourteen participants aged between 9 and 63 years have been enrolled in the trial. EDIT-101 was generally well tolerated with no dose-limiting toxicities, drug-related serious adverse events and ocular serious adverse events observed to date. Most adverse events (AEs) were mild (77%) or moderate (22%). 50% of AEs were related to the surgical procedure. 7/14 participants reported no ocular AEs related to EDIT-101. Five AEs of special interest were reported, mainly involving subretinal hyperreflective areas noted on OCT.
From his three stories, Dr. Pierce’s takeaway messages are the following:
- We can identify the genetic cause of disease for the majority of patients with IRDs. In 40% of patients, non-coding and structural mutations contribute to the disease.
- Understanding disease pathogenesis is important for effective use of genetic therapies.
- Genetically informed therapies show great promise for the treatment of IRDs: treatments need to be developed for all genetic forms of IRD. Our patients are counting on us.
Dr. Pierce thanked the ARVO community and concluded with Dr. Anthony Fauci’s parting advice: “Stick to the science.”
“I always speak the unvarnished truth to presidents and other senior government officials, even when such truths may be uncomfortable or politically inconvenient, because extraordinary things can happen when science and politics work hand in hand.”
And last but not least, Dr. Pierce ended his lecture by emotionally thanking his wife, two daughters and family.