Families and Scientists Meet to Discuss Therapy Development for People with RDH12 Mutations
Proof-of-concept for RDH12 gene therapy demonstrated in mouse model
On November 19, 2019, the Foundation Fighting Blindness and RDH12 family organizations convened a meeting of families, researchers, and representatives from biotech companies and the regulatory community to discuss the advancement of therapies for people with mutations in the gene RDH12, which cause Leber congenital amaurosis 13 (LCA 13).
The main goals of the meeting were to present and summarize the state of RDH12 pre-clinical and genetic research efforts, present the perspectives of affected individuals and their families, and identify needs and next steps for moving potential RDH12-associated therapies into clinical trials. Wiley Chambers, MD, a supervisory medical officer at the US Food & Drug Administration, provided valuable regulatory insights for RDH12 therapy development.
“We’re at an opportune juncture with RDH12 treatment development. Thanks to decades of research, we have preclinical proof-of-concept for gene replacement therapy in the RDH12 knockout mouse. Also, our clinical and genetic understanding of RDH12-associated disease has expanded,” said Ben Yerxa, PhD, chief executive officer, Foundation Fighting Blindness. “There’s more work to be done, but we are at a point where we can at least begin discussing potential clinical trial needs and design.”
“I am grateful to the RDH12 families who have worked so long and hard to fund critical research and raise awareness, and to the Foundation for bringing us together with the community of experts,” said Silvia Cerolini, whose daughter, Vicky, has LCA caused by RDH12 mutations. “The path forward is becoming clearer.”
I think we are close to the point where we can put stakes in the ground for a clinical trial
Deborah Thompson, PhD, Kellogg Eye Institute, University of Michigan, discussed her team’s work in RDH12 gene therapy development. The investigators showed that gene therapy protected the retinas for RDH12 knockout mice exposed to damaging levels of light. She noted that the high level of light exposure was necessary, because retinal degeneration was otherwise minimal for the mice.
Dr. Thompson and her team are also working to gain a better understanding of the function of the RDH12 enzyme and how reduced levels cause retinal degeneration. Thus far, they’ve determined that the disease correlates with the loss of RDH12 enzymatic activity and results in the accumulation of retinaldehydes, harmful byproducts from the metabolism of vitamin A in the visual cycle.
Though people with RDH12 mutations are usually referred to as having LCA, Bart LeRoy, MD, PhD, Children’s Hospital of Philadelphia, cautioned against labeling the associated disease as LCA, because many who are affected by mutations in the gene retain a significant amount of vision well into adulthood. He and other meeting participants believe that many adults with RDH12 mutations are genetically undiagnosed and identifying them would help populate natural history studies and clinical trials.
Four natural history studies for RDH12 patients were mentioned during the meeting, including a 38-patient study in China (Zou et al., 2018), a 30-family study in the EU, a 57-patient study in the US conducted by Abigail Fahim, MD, PhD, Kellogg Eye Institute, University of Michigan (Fahim et al., 2019), who was at the meeting, and another 21-patient study conducted in the US by Thomas Aleman (Aleman et al, 2018).
These and other studies have identified a common set of early manifestations of RDH12-associated retina disease resulting in poor vision, night blindness, nystagmus, and structural changes to the retina. However, these studies also identified a source of hope: Photoreceptors around the optic nerve are typically spared from the degeneration clearly evident in other regions. These intact photoreceptors can be targeted for treatment.
Regulatory approval for the RPE65 gene therapy LUXTURNA® in December 2017 has provided hope to the RDH12 community that a gene-therapy approach could be an effective approach to saving and possibly restoring vision for their patients. The development of LUXTURNA also highlighted the need to demonstrate treatment benefits that are relevant to patients. On this point, several attendees agreed that an outcome measure reflecting functional vision under different levels of light, like the multi-luminance mobility test (MLMT) used in the LUXTURNA clinical trial, might serve as a potentially useful outcome measure for RDH12 therapy clinical trials. However, since the MLMT is not appropriate for very young children, workshop participants discussed the need to develop age-appropriate tests such as sorting tasks under varied levels of light.
“We congratulate the RDH12 families and investigators for their commitment and progress in advancing research. Our meeting helped clarify the remaining steps that need to occur before potential therapies are ready for human study,” said Todd Durham, PhD, vice president of clinical outcomes and research at the Foundation Fighting Blindness. “I think we are close to the point where we can put stakes in the ground for a clinical trial.”