Gene Therapy of Retinal Dystrophies: Achievements, Challenges and Prospects

2008 ◽  
pp. 4-16 ◽  
Author(s):  
Dean Bok
Keyword(s):  
Gene Therapy ◽  
Retinal Dystrophies

scholarly journals Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

2010 ◽  
Vol 120 (9) ◽  
pp. 3042-3053 ◽  
Author(s):  
Anneke I. den Hollander ◽  
Aaron Black ◽  
Jean Bennett ◽  
Frans P.M. Cremers
Keyword(s):  
Gene Therapy ◽  
Retinal Dystrophies

Surgical Aspects in Gene Therapy for Inherited Retinal Diseases

2021 ◽  
Author(s):  
M. Dominik Fischer ◽  
Karl Ulrich Bartz-Schmidt ◽  
Spyridon Dimopoulos ◽  
Philipp Herrmann ◽  
Maximilian Gerhardt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Personalised Medicine ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Open Questions ◽  
Causal Therapy ◽  
Individual Step ◽  
Alternative Approaches ◽  
Surgical Aspects ◽  
Significant Milestone

AbstractInherited retinal dystrophies (IRD) have been studied since their recognition by Franz Donders and Albrecht von Graefe. It nevertheless took 100 years for a causal therapy to take shape in the form of gene therapy: The approval of Voretigen Neparvovec (VN) for the treatment of hereditary retinal dystrophies due to RPE65 mutations was thus a significant milestone – for the era of personalised medicine in general and ophthalmology in particular. The clinical management around gene therapy applications is complex and requires the cooperation of various experts as a multidisciplinary team. This article describes the requirements, challenges, approaches, and open questions regarding the surgical aspects of gene therapy for retinal dystrophies. The first part outlines the standard surgical treatment. Based on this standard, alternative approaches are indicated for each individual step and their value discussed. Knowledge gaps are defined and in the outlook we speculate on future developments.

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations

2014 ◽  
Vol 31 (4-5) ◽  
pp. 309-316 ◽  
Author(s):  
KERSTIN NAGEL-WOLFRUM ◽  
FABIAN MÖLLER ◽  
INESSA PENNER ◽  
UWE WOLFRUM
Keyword(s):  
Gene Therapy ◽  
Retinal Degeneration ◽  
Treatment Strategy ◽  
Viral Vectors ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Pharmacologic Treatment ◽  
Nonsense Mutations ◽  
Retinal Dystrophies ◽  
Retinal Disorders

AbstractThe eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30–50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.

scholarly journals Gene Therapy in Retinal Dystrophies

2019 ◽  
Vol 20 (22) ◽  
pp. 5722 ◽  
Author(s):  
Ziccardi ◽  
Cordeddu ◽  
Gaddini ◽  
Matteucci ◽  
Parravano ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Current Knowledge ◽  
Disease Genes ◽  
New Era ◽  
Gene Therapy Approach ◽  
Inherited Retinal Dystrophies ◽  
Diagnosis And Prognosis ◽  
Retinal Dystrophies ◽  
Degenerative Disorders

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated.

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