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

Award Number: R01EY034309
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $495,426 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	3	7/3/2025	NON-COMPETING CONTINUATION	$495,426
														Subtotal = $495,426

Issue Date FY: 2024 ( Subtotal = $494,721 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	2	7/22/2024	NON-COMPETING CONTINUATION	$494,721
														Subtotal = $494,721

Issue Date FY: 2023 ( Subtotal = $501,766 )
2023	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	1	9/19/2023	NEW	$501,766
														Subtotal = $501,766

Grand Total All Awards = $1,491,913

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

Award Number: R01EY034309

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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