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Viral vectors comprising rdh12 coding regions and methods of treating retinal dystrophies

A technology of RDH12, viral vector, applied in the direction of virus/phage, double-stranded DNA virus, single-stranded DNA virus, etc., can solve the problem that LCA has no known treatment method.

Pending Publication Date: 2020-11-03
RGT UNIV OF MICHIGAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Although ophthalmic conditions such as inherited retinal diseases are ubiquitous in humans and non-human mammals, and the genes encoding retinol dehydrogenase and the effects of some mutations in these genes are known, the RDH12 There is no known treatment for LCA caused by one or more mutations in

Method used

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  • Viral vectors comprising rdh12 coding regions and methods of treating retinal dystrophies
  • Viral vectors comprising rdh12 coding regions and methods of treating retinal dystrophies
  • Viral vectors comprising rdh12 coding regions and methods of treating retinal dystrophies

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example

[0048] The disclosed and claimed subject matter is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0049] Materials and methods

[0050] The following materials and methods were used in the experiments disclosed in the Examples listed below.

[0051] animal

[0052] Rdh12 has been previously - / - Generation and analysis of mice is described (Kurth et al., 2007). Rdh12 used in this study - / - Mice were bred by sibling mating between unfertilized egg males and females raised in our institutional animal facility. WT mice used in the study were C57BL / 6 from The Jackson Laboratory (Wilmington, MA).

[0053] Transgenic mice of the following genotype were used for the studies disclosed herein: Rdh12 homozygous for the Rpe65-Met450(M / M) variant on the C57BL / 6J background - / - Mice (Kurth, 2007), and albino Rdh12 homozygous for the Rpe65-Leu450(L / L) variant on a BALB / c background - / - Mice (Chrispell, 2009), o...

example 1

[0075] AAV-mediated expression of human RDH12

[0076] Various vectors for RDH12 replacement therapy were developed and tested. figure 2 Optimal RDH12 vector constructs are shown in A. The construct comprises a human RDH12 cDNA under the control of a human rhodopsin kinase (GRK1) promoter fragment. The constructs were packaged in the AAV2 / 5 serotype. AAV serotype 5 capsids have been shown to mediate photoreceptor transduction, but with slower kinetics and less stable expression than AAV8 capsids (Yang et al., 2002; Lotery et al., 2003; Allocca et al. et al., 2007; Lebherz et al., 2008). Inject AAV2 / 5-hGRK1p.hRDH12 (1.3×10 96 weeks after vg), expression of human RDH12 protein in mouse retina was assessed using antibodies specific for mouse RDH12 or human Rdh12 protein. The level of RDH12-like vector delivery appears to be roughly comparable to the amount of mouse Rdh12 ( figure 2 B). Native mouse Rdh12 and recombinant human RDH12 were assessed by indirect immunofluor...

example 2

[0083] Retinal damage caused by example 2AAV2 / 8

[0084] Retinal damage in mice injected with AAV2 / 8-hGRK1p.hRDH12.

[0085] A capsid derived from AAV serotype 8 has been shown to mediate efficient and robust transduction of photoreceptor cells (Allocca et al., 2007; Natkunarajah et al., 2008; Vandenberghe et al., 2011; Vandenberghe et al., 2013). Initial studies were performed with AAV2 / 8 serotypes carrying the vector constructs described above. to 10 8 -10 9 Dose of viral genomes (vg) by subretinal injection of AAV2 / 8-hGRK1p.hRDH12-treated Rdh12 - / - Mice enable robust expression of recombinant human RDH12 protein. However, the injected eyes began to show significant retinal damage as early as 3 weeks post-injection, and in almost all cases by 6 weeks post-injection. via CD68 + The presence of cells macrophage infiltration was observed in most cases ( Figure 9 ). From weaning to dying, towards Rdh12 - / - Continuous systemic administration of cyclosporine to mice (...

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Abstract

Provided are materials, methods and uses for treating an ophthalmological condition such as Leber Congenital Amaurosis by administering an effective amount of an adeno-associated virus AAV2, serotype5 (AAV 2 / 5) or AAV-5 comprising an expressible coding region for human RDH12.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to Provisional U.S. Patent Application Serial No. 62 / 586,624, filed November 15, 2017, which is incorporated herein by reference. [0003] Incorporation by reference of material submitted electronically [0004] As an independent part of the present disclosure, this application contains a sequence listing in computer readable form (file name: 51914A_Seqlisting.txt, created on November 9, 2018 (5,230 bytes, ASCII text file)), the entire content of which is incorporated by reference into this article. technical field [0005] The present disclosure relates to methods of medical treatment, e.g., for treating patients with ophthalmic conditions due to at least one loss-of-function mutation in the gene encoding the retinol dehydrogenase 12 protein (RDH12) (e.g., Leber's congenital A method for a human subject of Harmony), the method comprising administering to the subject an effective amo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/63A61K48/00C12N15/861
CPCA01K2217/075A01K2227/105A01K2267/0306A61K38/443A61K48/005A61K48/0058A61P27/02C12N7/00C12N15/86C12N2710/10043C12N2750/14143C12Y101/01105
Inventor D.A.汤普森R.R.阿利A.J.史密斯
Owner RGT UNIV OF MICHIGAN
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