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Sustained delivery of therapeutics to the visual system using genetically modified autologous mesenchymal stem cells to treat blinding diseases

Award Number: R01EY030081
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The objective of the proposed research is to evaluate the safety and efficacy of a novel method of delivering therapeutics to the central nervous system (CNS) and the retina to treat diseases associated with visual impairment. The hypothesis tested will be that autologous genetically modified mesenchymal stem cells (MSCs) can serve as effective vehicles for sustained delivery of therapeutics to visual centers in the brain and to the retina for the treatment of blinding diseases that result from pathology in one or more parts of the visual system. Proof of concept studies will be performed using a well-characterized and validated canine model of CLN2 neuronal ceroid lipofuscinosis, a disease with pediatric onset characterized by widespread neurodegeneration resulting in progressive loss of vision due to degeneration of both the retina and visual processing centers in the brain, cognitive and motor decline, and seizures. CLN2 disease is caused by mutations in TPP1, which result in deficiencies of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). It is hypothesized that providing TPP1 to the CNS using implantation of autologous MSCs that have been genetically modified to produce and secrete the protein will ameliorate disease-related vision loss in the canine model. To test this hypothesis, TPP1-producing MSCs will be injected into the vitreous of the eye and into the cerebrospinal fluid (CSF) of dogs affected by CLN2 disease. Based on previous studies, significant transfer of TPP1 from cells implanted in these locations to the retina and brain are anticipated, respectively. Functional vision will be evaluated in treated dogs using a novel iPad tablet based test that requires a choice between a screen displaying solid grey and a screen displaying a black and white stripe / grating pattern. Retinal function will be assessed with electroretinography, and retina-CNS interactions will be assessed with quantitative pupillometry. Dogs will also be monitored with established biomarkers of disease progression to determine if implantation of TPP1-producing MSCs results in amelioration of the neurological disease signs not directly associated with vision, preserves cognitive function, inhibits brain atrophy, and extends healthy lifespan when compared with control dogs. In addition, assessed will be the safety, persistence, and distribution of the implanted MSCs and the TPP1 enzyme they produce through histopathologic and immunohistochemical analysis of CNS tissues. Successful accomplishment of these aims will set the groundwork for testing this approach to therapy in children suffering from CLN2 disease and similar lysosomal storage disorders. It will also serve as the prototype for adopting this approach to treat many other diseases affecting the CNS and retina.


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: 2023 ( Subtotal = $533,836 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	5	4/27/2023	NON-COMPETING CONTINUATION	$378,466
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	001	5	4/28/2023	SUPPLEMENT FOR EXPANSION	$155,370
														Subtotal = $533,836

Issue Date FY: 2022 ( Subtotal = $521,022 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	001	4	5/6/2022	SUPPLEMENT FOR EXPANSION	$155,370
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	4	4/29/2022	NON-COMPETING CONTINUATION	$365,652
														Subtotal = $521,022

Issue Date FY: 2021 ( Subtotal = $464,195 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	3	4/20/2021	NON-COMPETING CONTINUATION	$464,195
														Subtotal = $464,195

Issue Date FY: 2020 ( Subtotal = $536,024 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	001	2	4/27/2020	NON-COMPETING CONTINUATION	$477,524
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Dietary Supplement Research Program	000	1	12/9/2019	SUPPLEMENT FOR EXPANSION	$58,500
														Subtotal = $536,024

Issue Date FY: 2019 ( Subtotal = $310,000 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	1	4/22/2019	NEW	$310,000
														Subtotal = $310,000

Grand Total All Awards = $2,365,077

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Sustained delivery of therapeutics to the visual system using genetically modified autologous mesenchymal stem cells to treat blinding diseases

Award Number: R01EY030081

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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