Overview of Retinal Gene Therapy: Current Status and Future Challenges

Bennett, Jean

doi:10.1101/cshperspect.a041278

Cited by 8 publications

(3 citation statements)

References 48 publications

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“…Significant progress has been achieved recently in the field of gene therapy for deafness [45][46][47][48] and blindness 14,26,[49][50][51] . This progress has usually involved gene-addition therapy, which has proven effective for small genes with coding sequence that can be accommodated within a single AAV vector (<4.7kb).…”

Section: Discussionmentioning

confidence: 99%

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PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F

Ivanchenko,

Hathaway,

Mulhall

et al. 2023

Preprint

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Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore a novel approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus (AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 in clinically relevant retinal models, including human retinal organoids and non-human primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.

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Section: Discussionmentioning

confidence: 99%

“…Clinically, USH1F is an attractive candidate for intervention by gene therapy: subretinal AAV therapy was approved for clinical use 25 and many other retinal gene therapies are in development 26 . However, the large coding sequence of PCDH15 constrains an AAV-based gene delivery.…”

Section: Introductionmentioning

confidence: 99%

PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F

Ivanchenko,

Hathaway,

Mulhall

et al. 2023

Preprint

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“…Although IRDs occur due to mutations in the causative gene, the exact molecular mechanisms remain unclear, and more effective treatment strategies are to be discovered [ 114 , 115 ]. With advances in high-throughput sequencing technology, genomics, epigenomics, transcriptomics, proteomics, metabolomics, and single cell-omics are frequently used in research to better understand biological processes at the gene, protein, and metabolic levels and discover new biomarkers and therapeutic targets [ 116 ].…”

Section: Future Trendsmentioning

confidence: 99%

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Liang,

Sun,

Duan

et al. 2023

Stem Cell Res Ther

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Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic diseases have long been used as a primary research tool to decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, are considered a promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, and best vitelliform macular dystrophy. Here, this paper focuses on the status of patient-derived iPSCs and organoids in IRDs in recent years concerning disease modeling and therapeutic exploration, along with potential challenges for translating laboratory research to clinical application. Finally, the importance of human iPSCs and organoids in combination with emerging technologies such as multi-omics integration analysis, 3D bioprinting, or microfluidic chip platform are highlighted. Patient-derived retinal organoids may be a preferred choice for more accurately uncovering the mechanisms of human retinal diseases and will contribute to clinical practice.

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Systemic Treatment of Body‐Wide Duchenne Muscular Dystrophy Symptoms

Konieczny

2024

Clin Pharma and Therapeutics

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Duchenne muscular dystrophy (DMD) is a fatal X‐linked disease that leads to premature death due to the loss of dystrophin. Current strategies predominantly focus on the therapeutic treatment of affected skeletal muscle tissue. However, certain results point to the fact that with successful treatment of skeletal muscle, DMD‐exposed latent phenotypes in tissues, such as cardiac and smooth muscle, might lead to adverse effects and even death. Likewise, it is now clear that the absence of dystrophin affects the function of the nervous system, and that this phenotype is more pronounced when shorter dystrophins are absent, in addition to the full‐length dystrophin that is present predominantly in the muscle. Here, I focus on the systemic aspects of DMD, highlighting the ubiquitous expression of the dystrophin gene in human tissues. Furthermore, I describe therapeutic strategies that have been tested in the clinic and point to unresolved questions regarding the function of distinct dystrophin isoforms, and the possibility of current therapeutic strategies to tackle phenotypes that relate to their absence.

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Overview of Retinal Gene Therapy: Current Status and Future Challenges

Cited by 8 publications

References 48 publications

PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F

PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Systemic Treatment of Body‐Wide Duchenne Muscular Dystrophy Symptoms

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