Viral gene therapy approaches for CRB1 retinal disease

Boon, N.

Mutations in the CRB1 gene can cause retinal dystrophies such as Retinitis Pigmentosa or Leber Congenital Amaurosis . These patients experience progressive vision loss which ultimately leads to blindness. Currently, there are no treatment options available for these patients.
This thesis provides novel information on AAV.hCRB gene augmentation therapy in CRB1 mutant animal and human-derived models. We show the phenotype of (1) a novel mouse model with CRB2 ablation specifically in rod photoreceptor cells with loss of retinal function (Chapter 2), (2) a Crb1 mutant brown Norway rat with severe and early onset progressive vision loss (Chapter 3), (3) CRB1 patient-derived retinal organoids (Chapter 4), and (4) CRB1KO and CRB1KOCRB2+/- LCA-like retinal organoids (Chapter 5). Next, AAV-mediated gene augmentation was explored in Crb1 mutant rats (Chapter 3) and CRB1 patient-derived and CRB1KO LCA retinal organoids (Chapter 4 and 5). Finally, single-cell RNA sequencing was performed...Show moreMutations in the CRB1 gene can cause retinal dystrophies such as Retinitis Pigmentosa or Leber Congenital Amaurosis . These patients experience progressive vision loss which ultimately leads to blindness. Currently, there are no treatment options available for these patients.
This thesis provides novel information on AAV.hCRB gene augmentation therapy in CRB1 mutant animal and human-derived models. We show the phenotype of (1) a novel mouse model with CRB2 ablation specifically in rod photoreceptor cells with loss of retinal function (Chapter 2), (2) a Crb1 mutant brown Norway rat with severe and early onset progressive vision loss (Chapter 3), (3) CRB1 patient-derived retinal organoids (Chapter 4), and (4) CRB1KO and CRB1KOCRB2+/- LCA-like retinal organoids (Chapter 5). Next, AAV-mediated gene augmentation was explored in Crb1 mutant rats (Chapter 3) and CRB1 patient-derived and CRB1KO LCA retinal organoids (Chapter 4 and 5). Finally, single-cell RNA sequencing was performed on AAV.hCRB treated CRB1 patient-derived retinal organoids (Chapter 4). To our knowledge this is the first time that an improved phenotype after AAV.hCRB gene augmentation in CRB1 RP patient-derived and CRB1KO LCA retinal organoids is observed, providing essential information for future gene therapy possibilities in patients with a mutation in the CRB1 gene.
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Viral gene therapy approaches for CRB1 retinal disease