NIH grant: Developing a gene therapy for IMPG2-Associated Retinal Degeneration in a knockout mouse model (1F31EY039091-01)

retained text

NIH grant 1F31EY039091-01: Developing a gene therapy for IMPG2-Associated Retinal Degeneration in a knockout mouse model
Institute: {'code': 'EY', 'abbreviation': 'NEI', 'name': 'National Eye Institute', 'admin_org_id': '12500073', 'admin_funding_url': ''}. PI: Katherine  Descant. Award: $41404.
Start: 2026-08-01T00:00:00.
Abstract
IMPG2-associated retinal degeneration (IMPG2-RD) is an inherited form of progressive vision loss. IMPG2 is a
crucial extracellular matrix protein that maintains photoreceptor structure and function, thus deleterious
mutations result in photoreceptor cell death. Biallelic mutations in IMPG2 cause a severe, early-onset form of
retinal degeneration that includes early macular involvement, while monoallelic mutations result in a later-onset
form of IMPG2-RD characterized by macular vitelliform lesions and vision loss that is milder than the biallelic
disease. No treatment is currently available for either form of IMPG2-RD. However, here, I propose to engineer
a sight-preserving therapy that uses adeno-associated viruses (AAV) to deliver a functional IMPG2 cDNA
sequence to photoreceptors. Towards this goal, the Philpot Lab has developed an Impg2-knockout (Impg2-KO)
mouse line that recapitulates key features of the human disease and can therefore be a testbed for therapeutic
development. Although adult Impg2-KO mice display well-characterized retinal thinning and vitelliform-like
subretinal deposits, early disease progression has not yet been studied in detail. Completion of an early
timepoint-focused natural history characterization of this mouse model is anticipated to clarify the early cellular
dysregulation in IMPG2-RD that precedes photoceptor death and to reveal early biomarkers of disease (Aim
1). Identified early biomarkers can be leveraged to accelerate the evaluation of the proposed viral-mediated
gene therapy (Aim 2). Together, these two Aims serve to test my central hypothesis that a gene augmentation
approach can preserve retinal structure and function in Impg2-KO mice. This work will provide critical insights
into early IMPG2-RD pathology, and in fulfilment of the present unmet need, will support the development of a
therapeutic for patients.

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