Prospects for gene therapy of inherited retinal disease

Bainbridge, James

doi:10.1038/eye.2008.412

Cited by 9 publications

(12 citation statements)

References 42 publications

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“…It shows an immune privilege, has transparency, and provides easy accessibility. Several different gene therapeutic strategies have been developed to treat inherited ocular diseases [Bainbridge, 2009; Stone, 2009] and important progress has been made using gene replacement therapy in human. Efficiency and safety has been shown in clinical trials for patients with Leber's congenital amourosis type 2 (LCA2; MIM♯ 204100), a disease that involves retinal degeneration and severe vision loss in early childhood [Bainbridge et al, 2008; Cideciyan et al, 2008; Hauswirth et al, 2008; Maguire et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation

et al. 2011

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Bardet-Biedl syndrome (BBS) is a multisystem disorder caused by ciliary defects. To date, mutations in 15 genes have been associated with the disease and BBS1 is most frequently affected in patients with BBS. The use of homozygosity mapping in a large consanguineous family allowed us to identify the splice donor site (SD) mutation c.479G>A in exon 5 of BBS1. Clinically affected family members show symptoms of retinitis pigmentosa (RP) but lack other primary features that would clearly support the diagnosis of BBS. In agreement with this exceptionally mild BBS1-associated phenotype, we did not detect obvious ciliary defects in patient-derived cells. SDs are bound by the U1 small nuclear RNA (U1), a process that initiates exon recognition during splicing. The mutation described herein interferes with U1 binding and induces aberrant splicing of BBS1. For a gene therapeutic approach, we have adapted the sequence of U1 to increase its complementarity to the mutated SD. Lentiviral treatment of patient-derived fibroblasts with the adapted U1 partially corrected aberrant splicing of endogenously expressed BBS1 transcripts. This therapeutic effect was dose-dependent. Our results show that the adaptation of U1 can correct pathogenic effects of splice donor site mutations and suggest a high potential for gene therapy.

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Section: Discussionmentioning

confidence: 99%

U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation

et al. 2011

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“…If so, visual function may improve even with long-standing optic atrophy. That this may be possible is suggested by the Leber's congenital amaurosis (LCA) clinical trials where partial return of visual function occurred even in eyes with severe and long-standing photoreceptor loss [97, 120, 121]. …”

Section: Candidates For Genetic Therapiesmentioning

confidence: 99%

Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

Koilkonda

Guy

2011

Journal of Ophthalmology

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Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

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“…Although the protocols of the three trials presented important differences (promoter, doses), they have already established proof of principle of gene therapy for inherited retinal disease and will pave the way for the development of gene therapy approaches for a broad range of eye disorders. (Bainbridge 2009), which represents an important opportunity for scientists working in the mitochondrial field.…”

Section: Strategies Developed For Gene Therapy For Mtdna Disordersmentioning

confidence: 99%

“…The eye has unique advantages as a target organ for gene therapy. Its compartmentalized anatomy enables local vector delivery with low systemic dissemination and is accessible for in vivo assessment by optical imaging and electrophysiological techniques (Bainbridge 2009). Therefore, the prospect of blindness prevention caused by mitochondrial impairment represents an impelling and achievable challenge within the current arena of biomedical research, as shown by the recent reports of clinical trials for the inherited retinal degeneration Leber congenital amaurosis (LCA).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial medicine: to a new era of gene therapy for mitochondrial DNA mutations

Cwerman-Thibault

Sahel

Corral‐Debrinski

2010

J of Inher Metab Disea

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Mitochondrial disorders can no longer be ignored in most medical disciplines. Such disorders include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions also play a role in the aging process. Despite progresses made in identification of their molecular bases, nearly everything remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has >20 years of history around the world. We are involved, as are many other laboratories, in the challenge of finding ways to fight these diseases. However, our main limitation is the scarcety of animal models required for both understanding the molecular mechanisms underlying the diseases and evaluating therapeutic strategies. This is especially true for diseases due to mutations in mitochondrial DNA (mtDNA), since an authentic genetic model of mtDNA mutations is technically a very difficult task due to both the inability of manipulating the mitochondrial genome of living mammalian cells and to its multicopy nature. This has led researchers in the field to consider the prospect of gene therapy approaches that can roughly be divided into three groups: (1) import of wild-type copies or relevant sections of DNA or RNA into mitochondria, (2) manipulation of mitochondrial genetic content, and (3) rescue of a defect by expression of an engineered gene product from the nucleus (allotopic or xenotropic expression). We briefly introduce these concepts and indicate where promising progress has been made in the last decade.

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Prospects for gene therapy of inherited retinal disease

Cited by 9 publications

References 42 publications

U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation

U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation

Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

Mitochondrial medicine: to a new era of gene therapy for mitochondrial DNA mutations

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