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Compositions and methods for treatment of dominant retinitis pigmentosa

A technology of retinal pigments and compositions, applied in biochemical equipment and methods, gene therapy, using vectors to introduce foreign genetic material, etc.

Pending Publication Date: 2021-01-08
UNIV OF FLORIDA RES FOUNDATION INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no approved drugs or gene therapy treatments for adRP

Method used

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  • Compositions and methods for treatment of dominant retinitis pigmentosa
  • Compositions and methods for treatment of dominant retinitis pigmentosa
  • Compositions and methods for treatment of dominant retinitis pigmentosa

Examples

Experimental program
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Embodiment 1

[0109] Hereditary retinal degenerations are caused by mutations in >250 genes that affect photoreceptor cells or the retinal pigment epithelium and cause vision loss. For autosomal recessive and X-linked retinal degenerations, remarkable progress has been made in the field of gene therapy, as evidenced by the increasing number of clinical trials and the recent commercialization of the first gene therapy for congenital forms of blindness. However, despite enormous efforts to develop treatments for the most common form of autosomal dominant retinitis pigmentosa (adRP), caused by mutations in >150 rhodopsin (RHO) genes, translation to the clinic has been slow. Stand still. Here, for the first time, a highly potent novel short hairpin RNA (shRNA) targeting human (and canine) RHO in a mutation-independent manner is identified. This shRNA was combined with a human RHO surrogate cDNA made resistant to RNA interference in a single adeno-associated virus (AAV) vector, and this constru...

Embodiment 2

[0174] Example 2: Constructs protect mice from retinal degeneration

[0175] AAV-shRNA 820 -RHO 820 The constructs provided long-term protection against retinal degeneration in the RHO-adRP mouse model.

[0176] C57Bl / 6 mice transgenic for human P23H RHO undergo retinal degeneration due to the presence of the mutant rhodopsin gene even in the presence of dim red light without exposure to bright light (33, 34, 43). At 1 month of age, mice of this genotype were treated with AAV2 / 5-GFP or scAAV2 / 5-RHO 820 -shRNA 820 Subretinal injections were administered in one eye. Two groups of mice were analyzed at different intervals: a) before treatment, b) 1 month after injection, c) 2 months after injection, and d) 3 months after injection. Subretinal injection induced transient retinal detachment, which eventually resolved. The fellow eye was not treated.

[0177] OCT analysis was performed at monthly intervals for three months in P23H RHO mice to determine the effect of vehicle t...

Embodiment 3

[0186] Example 3: Analysis of mRNA Sequences Expressed by Vector Constructs

[0187] To determine the type of short mRNA sequences derived from AAV constructs, scAAV2 / 5-RHO 820 -shRNA 820 The construct transfected HEK293T cells. After 48 hours, total RNA was extracted. Extracted RNA was size fractionated and short RNA sequences were subjected to RNA sequencing. for shRNA 820 RNA molecules of their sequence are analyzed to determine their size as well as their 5' and 3' ends (see Figure 24 ).

[0188] A summary of the sequencing reads is shown in Figure 25 middle. The sequence (UAG) at the 5' end of the guide strand in 73% of the RNA molecules was identical to the expected sequence. 13% of the molecules were shortened by one nucleotide at the 5' end. 52% had 2 extra uridines at the 3' end, while 10% had 1 extra uridine at the 3' end. 13% of the molecules had an extra UUA codon at the 3' end. SEQ ID NO: 40 to 46 are provided as derived from shRNA 820 Sequences of t...

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Abstract

Aspects of the disclosure relate to methods and compositions useful for treating retinitis pigmentosa. In some aspects, the disclosure provides compositions and methods for delivering an interfering RNA to a subject in order to reduce expression of one or both alleles of an endogenous RHO gene (for example a mutant rho allele associated with retinitis pigmentosa) in a subject. In some embodiments,a replacement RHO coding sequence that is resistant to the interfering RNA also is delivered to the subject.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the filing dates of U.S. Provisional Application No. 62 / 679,585, filed June 1, 2018, and U.S. Provisional Application No. 62 / 809,539, filed February 22, 2019, the entire contents of each of which are incorporated by reference enter. Background technique [0003] Autosomal dominant retinitis pigmentosa (adRP) is a blinding disease that affects 1 in 12,000 people. A significant proportion of these individuals carried mutations in the rhodopsin gene (RHO), the light harvesting pigment protein of photoreceptor cells in the retina. The disease is dominant because inheritance of the mutated gene from either parent results in retinal degeneration and eventual blindness. More than 100 different mutations identified in RHO cause blindness. There are currently no approved drugs or gene therapy treatments for adRP. Accordingly, there is a need for effective treatment options for any and al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/79C12N15/86C12N15/85C12N15/10C12N15/11C12N15/113C07H21/02
CPCC12N15/1138C12N2310/14C12N2320/32C12N2310/121C12N2750/14143A01K2217/072A01K2227/105A01K2267/0306C12N2310/531C12N15/86C12N2310/122C12N2750/14142
Inventor 阿尔弗雷德·S·莱温威廉·W·豪斯维特迈克尔·T·马森吉尔威廉·贝尔特兰古斯塔沃·D·阿吉雷阿图尔·西代西扬塞缪尔·雅各布森
Owner UNIV OF FLORIDA RES FOUNDATION INC
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