Mitigating retinitis pigmentosa based on a non-invasive rod energy-landscape biomarker

Project Summary / Abstract: Retinitis pigmentosa (RP) is a disease that leads to untreatable and
irreversible cone death and blindness. A myriad of loss-of-function mutations, including in transducin 1 or
phosphodiesterase 6 genes, underlie RP. Ex vivo studies from experimental models support abnormal
mitochondria performance as a common pathogenic condition leading to RP pathology. However,
evaluating such mitochondrial abnormalities in patients is not possible and a one-therapy-fits-all approach
is unlikely to improve outcomes patient diversity. Addressing these major knowledge gaps will require a
patient-friendly, non-invasive biomarker of mitochondria performance.
Recently, we discovered a novel index of mitochondria performance based on a feature that is
readily identifiable in optical coherence tomography (OCT), the inner segment ellipsoid zone (ISez). Our
first-in-kind studies in wild-type mice show that the shape of the ISez profile changes from elongated
during a low energy demand condition (light) to rounder during a high energy demand condition (dark).
The underlying mitochondria etiology of the change in ISez profile shape is supported by electron
microscopy and oxygen consumption rate measurements in two mice strains with distinct mitochondria
activity. For example, OCT examination of cyclic-light reared 2-month-old mice with a mutation in the α
subunit of transducin 1 (Gnat1rd17) shows modest rod loss with a rounder-than-normal ISez and higher rate
of oxygen consumption than in the dark, biomarker evidence for early mitochondria overperformance.
Also, at postnatal (P) day 23, dark-reared mice with a mutation in the rod phosphodiesterase 6b gene
(Pde6brd10) show modest rod loss together with rounder-than-normal ISez when examined in the dark,
biomarker evidence for mitochondria overperformance. When P23 dark-reared Pde6brd10 mice are
exposed to room light for 1 hour they showed a more-elliptical-than-normal ISez shape suggesting rod
mitochondria underperformance. This is notable because, whilst the 1 hour of light did not cause
immediate additional rod death, accelerated rod loss reportedly occurs days later after continued dark-
rearing. These considerations show that the ISez profile shape is sensitive to abnormalities in the rod
energy landscape that precede later rod loss. The natural history of change of the ISez profile shape as it
relates to rod atrophy in cyclic-light reared Gnat1rd17 or Pde6brd10 mice is unknown.
Our working hypothesis is that restoring our mitochondria performance biomarker (the ISez profile
shape) to wild-type-like levels predicts pro-survival treatment outcomes in experimental IRD. These
studies introduce an innovative and clinically relevant imaging biomarker, the ISez profile shape, for
assessing treatment efficacy in RP/IRD. Therapies that restore the ISez profile shape to normal are
ultimately expected to prevent loss of sight in patients with IRD.

Grant Number: 5R01EY034309-03
NIH Institute/Center: NIH
Principal Investigator: BRUCE BERKOWITZ