IP Library › Granted Patent US 12,203,074
Granted Patent B2
US 12,203,074 · App. 17/059,815 · Granted Jan 21, 2025

Compositions and methods for treatment of dominant retinitis pigmentosa

Inventors: Alfred S. Lewin (Gainesville, FL); William W. Hauswirth (Gainesville, FL); Michael T. Massengill (Gainesville, FL); William Beltran (Wynnewood, PA); Gustavo D. Aguirre (Media, PA); Artur Cideciyan (Lafayette Hill, PA); Samuel Jacobson (Penn Valley, PA)
Assignees: University of Florida Research Foundation, Incorporated; The Trustees of the University of Pennsylvania
C12N15/1138C12N15/86C12N2310/121C12N2310/122C12N2310/14C12N2320/32C12N2750/14142C12N2750/14143
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Quick Facts
Patent No.
US 12,203,074
App. No.
17/059,815
Granted
Jan 21, 2025
Kind
B2
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.

Claims (20)

1. A short hairpin RNA (shRNA) comprising the nucleotide sequence: GUGGCAUUCUACAUCUUCAUUCAAGAGAUGAAGAUGUAGAAUGCCAC (SEQ ID NO: 4).

2. A vector encoding the shRNA of claim 1 .

3. The vector of claim 2 , further comprising a recombinant rhodopsin (RHO) coding sequence that does not contain a sequence targeted by the shRNA.

4. The vector of claim 3 , wherein the recombinant RHO coding sequence is codon-optimized for expression in a human cell.

5. The vector of claim 3 , wherein the recombinant RHO coding sequence comprises a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 5.

6. The vector of claim 5 , wherein the recombinant RHO coding sequence comprises the nucleotide sequence of SEQ ID NO: 5.

7. The vector of claim 3 , further comprising an opsin proximal promoter.

8. The vector of claim 7 , wherein the opsin proximal promoter comprises the nucleotide sequence of SEQ ID NO: 7.

9. The vector of claim 2 , wherein the vector is a plasmid.

10. The vector of claim 2 , wherein the vector is a recombinant adeno-associated viral (rAAV) vector.

11. The vector of claim 10 , wherein the rAAV vector is self-complementary.

12. The vector of claim 2 , further comprising an H1 RNA promoter.

13. The vector of claim 12 , wherein the H1 RNA promoter comprises the nucleotide sequence of SEQ ID NO: 8.

14. A recombinant adeno-associated viral (rAAV) particle comprising the rAAV vector of claim 10 .

15. A composition comprising the rAAV particle of claim 14 and a pharmaceutically acceptable carrier.

16. A method of modulating RHO expression in a subject, the method comprising administering subretinally to the subject the composition of claim 15 .

17. A method of treating retinitis pigmentosa in a subject, the method comprising administering subretinally to the subject the composition of claim 15 .

18. The method of claim 17 , wherein the subject is a human subject.

19. A vector comprising a nucleotide sequence that is at least 90% identical to the nucleotide sequence of SEQ ID NO: 6.

20. The vector of claim 19 , wherein the vector comprises the nucleotide sequence of SEQ ID NO: 6.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded Jul 17, 2023
From: HERCULES CAPITAL, INC.
To: IVERIC BIO, INC.; IVERIC BIO GENE THERAPY LLC; ORION OPHTHALMOLOGY LLC
Reel/Frame 064286/0472 →
SECURITY INTEREST Recorded Aug 5, 2022
From: IVERIC BIO, INC.
To: HERCULES CAPITAL, INC.
Reel/Frame 061088/0048 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 19, 2021
From: BELTRAN, WILLIAM; AGUIRRE, GUSTAVO D.; JACOBSON, SAMUEL; CIDECIYAN, ARTUR
To: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
Reel/Frame 055652/0633 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 5, 2021
From: LEWIN, ALFRED S.; HAUSWIRTH, WILLIAM W.; MASSENGILL, MICHAEL T.
To: UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED
Reel/Frame 055509/0726 →
Continuity (3)
Provisional Application 62809539 · Feb 22, 2019
Provisional Application 62679585 · Jun 1, 2018
Related Publication 20210207147A1 · Jul 8, 2021
References Cited (70)
US 7138378B1 · Farrar et al. · 2006 [cited by applicant]
US 8450473B2 · Sullivan · 2013 [cited by examiner]
US 8551970B2 · Farrar et al. · 2013 [cited by applicant]
US 11118185B2 · Lewin et al. · 2021 [cited by applicant]
US 20070009899A1 · Mounts · 2007 [cited by applicant]
US 20130064815A1 · Coller · 2013 [cited by applicant]
US 20150159171A1 · Deglon · 2015 [cited by applicant]
US 20170096683A1 · Scaria · 2017 [cited by examiner]
US 20170173183A1 · O'Riordan et al. · 2017 [cited by applicant]
US 20170348387A1 · Aquirre et al. · 2017 [cited by applicant]
US 20180043034A1 · Pierce et al. · 2018 [cited by applicant]
US 20190093111A1 · Lewin et al. · 2019 [cited by applicant]
US 20210324387A1 · Lewin et al. · 2021 [cited by applicant]
CN 102061305A · 2011 [cited by applicant]
CN 102061308A · 2011 [cited by applicant]
CN 102061305B · 2012 [cited by examiner]
CN 105960413A · 2016 [cited by applicant]
JP 2006523464A · 2006 [cited by applicant]
JP 2007530431A · 2007 [cited by applicant]
JP 2010518821A · 2010 [cited by applicant]
WO WO2004020631A2 · 2004 [cited by applicant]
WO WO2004022722A2 · 2004 [cited by examiner]
WO WO2004094606A2 · 2004 [cited by applicant]
WO WO2005090572A2 · 2005 [cited by applicant]
WO WO2008100627A2 · 2008 [cited by applicant]
WO WO2008125846A2 · 2008 [cited by applicant]
WO WO2009035792A1 · 2009 [cited by applicant]
WO WO2010127209A2 · 2010 [cited by applicant]
WO WO2014138792A1 · 2014 [cited by applicant]
WO WO2015075154A2 · 2015 [cited by applicant]
WO WO2015143418A2 · 2015 [cited by applicant]
WO WO2016138353A1 · 2016 [cited by applicant]
WO WO2016176690A2 · 2016 [cited by applicant]
WO WO2017137493A1 · 2017 [cited by applicant]
WO WO2017151823A1 · 2017 [cited by applicant]
Massengill et al., “Tandem Delivery of Short Hairpin RNAs and Rhodopsin cDNA to Combat Retinal Degeneration in Autosomal Dominant Retinitis Pigmentosa”, IOVS, vol. 58, 4082, Published Jun. 2017. (Year: 2017). [cited by examiner]
Palfi et al., “Adeno-Associated Virus-Mediated Rhodopsin Replacement Provides Therapeutic Benefit in Mice with a Targeted Disruption of the [cited by examiner]
Plotkin et al., “Tissue-specific codon usage and the expression of human genes”, PNAS, vol. 101, Published Aug. 24, 2004, pp. 12588-12591. (Year: 2004). [cited by examiner]
Latella et al., “In vivo editing of human mutant [cited by examiner]
Bethke, “The Future of Gene Therapy”, Review of Opthalmology, Published Apr. 5, 2016, retrieved on Jun. 27, 2024, retrieved from the Internet: < https://www.reviewofophthalmology.com/article/the-future-of-gene-therapy>.… [cited by examiner]
Supplementary Partial European Search Report for Application No. EP 17760752.0, mailed Jul. 5, 2019. [cited by applicant]
Extended European Search Report for Application No. EP 17760752.0, mailed Oct. 15, 2019. [cited by applicant]
Extended European Search Report for Application No. EP 22170988.4, mailed Dec. 19, 2022. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/US2017/020289, mailed Jul. 19, 2017. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/US2017/020289, mailed Sep. 13, 2018. [cited by applicant]
Extended European Search Report for Application No. EP 19812143.6 mailed Sep. 16, 2022. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/US2019/035159, mailed Sep. 12, 2019. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/US2019/035159 mailed Dec. 10, 2020. [cited by applicant]
[No Author Listed], GenBank Accession No. M55171.2. Mouse opsin (MOPS) gene, complete cds. Jun. 9, 2017. 4 pages. [cited by applicant]
Athanasiou et al., The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Prog Retin Eye Res. Jan. 2018:62:1-23. doi: 10.1016/j.preteyeres.2017.10.002. Epub Oct. 16,… [cited by applicant]
Behrman et al., A CHOP-regulated microRNA controls rhodopsin expression. J Cell Biol. Mar. 21, 2011; 192(6):919-27. doi: 10.1083/jcb.201010055. Epub Mar. 14, 2011. [cited by applicant]
Beltran et al., Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations. Mol Ther. Aug. 2, 2017;25(8):1866-1880. doi: 10.1016/j.ymthe.2017.05.004. Epub May 27, 2017. [cited by applicant]
Bennett et al., Taking Stock of Retinal Gene Therapy: Looking Back and Moving Forward. Mol Ther. May 3, 2017;25(5):1076-1094. doi: 10.1016/j.ymthe.2017.03.008. Epub Apr. 5, 2017. [cited by applicant]
Brummelkamp et al., A system for stable expression of short interfering RNAs in mammalian cells. Science. Apr. 19, 2002;296(5567):550-3. doi: 10.1126/science.1068999. Epub Mar. 21, 2002. [cited by applicant]
Burnight et al., Using CRISPR-Cas9 to Generate Gene-Corrected Autologous iPSCs for the Treatment of Inherited Retinal Degeneration. Mol Ther. Sep. 6, 2017;25(9):1999-2013. doi: 10.1016/j.ymthe.2017.05.015. Epub Jun. 12,… [cited by applicant]
Cashman et al., Towards mutation-independent silencing of genes involved in retinal degeneration by RNA interference. Gene Ther. Aug. 2005;12(15):1223-8. doi: 10.1038/sj.gt.3302512. [cited by applicant]
Dunbar et al., Gene therapy comes of age. Science. Jan. 12, 2018;359(6372):eaan4672. doi: 10.1126/science.aan4672. [cited by applicant]
Froebel et al., Effects of Pathogenic Variations in the Human Rhodopsin Gene (hRHO) on the Predicted Accessibility for a Lead Candidate Ribozyme. Invest Ophthalmol Vis Sci. Jul. 1, 2017; 58(9):3576-3591. doi: 10.1167/io… [cited by applicant]
Gorbatyuk et al., Suppression of mouse rhodopsin expression in vivo by AAV mediated siRNA delivery. Vision Res. Apr. 2007;47(9):1202-8. doi: 10.1016/j.visres.2006.11.026. Epub Feb. 12, 2007. PMID: 17292939; PMCID: PMC18… [cited by applicant]
Guziewicz et al., BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. Proc Natl Acad Sci U S A. Mar. 20, 2018;115(12):E2839-E2848. doi: 10.1073/pnas.1720662115. Epub Mar. 5, 20… [cited by applicant]
Iwabe et al., Assessment of visual function and retinal structure following acute light exposure in the light sensitive T4R rhodopsin mutant dog. Exp Eye Res. May 2016;146:341-353. doi: 10.1016/j.exer.2016.04.006. Epub … [cited by applicant]
Jiang et al., Retinitis pigmentosa associated [cited by applicant]
Lewin et al., Gene augmentation for adRP mutations in RHO. Cold Spring Harb Perspect Med. Jul. 18, 2014;4(9):a017400. doi: 10.1101/cshperspect.a017400. [cited by applicant]
Mao et al., Long-term rescue of retinal structure and function by rhodopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice. Hum Gene Ther. Apr. 2012;23(4):356-66. doi: 10.1089/hu… [cited by applicant]
Millington-Ward et al., Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa. Mol Ther. Apr. 2011;19(4):642-9. doi: 10.1038/mt.2010.293. Epub Jan. 11… [cited by applicant]
Murray et al., Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration. Invest Ophthalmol Vis Sci. Oct. 2015; 56(11):6362-75. doi: 10.1167/iovs.15-16400. [cited by applicant]
O'Keefe, siRNAs and shRNAs: Tools for protein knockdown by gene silencing. Mater Methods. 2013;3(197). Jul. 7, 2017 (Jul. 7, 2017), XP055956975, Retrieved from the Internet: URL:https://web.archive.org/web/2017070717184… [cited by applicant]
Rosas et al., Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol Ther. Nov. 2012; 20(11):2098-110. doi: 10.1038/mt.2012.197. Epub Sep. 18, 2012. [cited by applicant]
Stanton et al., Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration. Sci Rep. Sep. 22, 2017;7(1):12147. doi: 10.1038/s41598-017-11898-3. [cited by applicant]
Sudharsan et al., Acute and Protracted Cell Death in Light-Induced Retinal Degeneration in the Canine Model of Rhodopsin Autosomal Dominant Retinitis Pigmentosa. Invest Ophthalmol Vis Sci. Jan. 1, 2017;58(1):270-281. do… [cited by applicant]