Granted Patent
B2
US 12,728,171 · App. 17/415,860 · Granted Sep 8, 2026
Complement factor I and complement factor I cofactor, vectors encoding therefor and therapeutic use
Inventors:
Anna Dreismann (Stevenage, GB); Scott Ellis (Stevenage, GB); Josephine Heather Lucienne Joel (Stevenage, GB)
Assignee:
NOVARTIS PHARMACEUTICALS UK LIMITED
View Patent ↗
Loading inventors, assignments & file history…
Abstract
A product comprising (i) a Complement Factor I (CFI) cofactor; and (ii) Complement Factor I (CFI), or nucleotide sequences encoding therefor, as a combined preparation for simultaneous, separate or sequential use in therapy.
Claims (22)
1 . An isolated polynucleotide comprising nucleotide sequences encoding (i) a Complement Factor I (CFI) cofactor; and (ii) Complement Factor I (CFI), wherein the polynucleotide comprises:
a) a 5′ AAV ITR;
b) a CMV promoter;
c) a codon-optimized nucleotide sequence encoding Complement Factor H Like Protein 1 (FHL1);
d) a linker comprising a self-cleaving 2A peptide sequence;
e) a codon-optimized nucleotide sequence encoding CFI;
f) a WPRE3 regulatory element;
g) a Bovine Growth Hormone poly-A signal; and
h) a 3′ AAV ITR;
wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 22 or 23, or a nucleotide sequence that has at least 95% sequence identity thereto.
2 . The isolated polynucleotide of claim 1 , wherein: (a) the nucleotide sequence encoding FHL1 is SEQ ID NO: 12; and/or (b) the nucleotide sequence encoding CFI is SEQ ID NO: 10.
3 . The isolated polynucleotide of claim 1 , wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 22 or 23.
4 . The isolated polynucleotide of claim 1 , wherein the polynucleotide is less than or equal to 4.7 kb.
5 . A vector comprising the polynucleotide of claim 1 .
6 . The vector of claim 5 , wherein the vector is an adeno-associated viral (AAV) vector.
7 . The vector of claim 5 , wherein the vector is in the form of a viral vector particle.
8 . The vector of claim 7 , wherein the AAV vector particle comprises AAV2 or AAV8 capsid proteins.
9 . A cell comprising the polynucleotide of claim 1 .
10 . A cell transduced with the vector of claim 5 .
11 . A pharmaceutical composition comprising the polynucleotide of claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient.
12 . The isolated polynucleotide of claim 1 , wherein: (a) the nucleotide sequence encoding FHL1 is SEQ ID NO: 12; and (b) the nucleotide sequence encoding CFI is SEQ ID NO: 10.
13 . The isolated polynucleotide of claim 1 , wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 22.
Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 18, 2026
From: GYROSCOPE THERAPEUTICS LIMITED
To: NOVARTIS PHARMACEUTICALS UK LIMITED
Reel/Frame 073824/0864 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 22, 2025
From: GYROSCOPE THERAPEUTICS LIMITED
To: NOVARTIS PHARMACEUTICALS UK LIMITED
Reel/Frame 072639/0145 →
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE ADDRESS PREVIOUSLY RECORDED AT REEL: 056613 FRAME: 0753. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT .
Recorded Jul 1, 2021
From: DREISMANN, ANNA; ELLIS, SCOTT; JOEL, JOSEPHINE HEATHER LUCIENNE
To: GYROSCOPE THERAPEUTICS LIMITED
Reel/Frame 057348/0005 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 22, 2021
From: DREISMANN, ANNA; ELLIS, SCOTT; JOEL, JOSEPHINE HEATHER LUCIENNE
To: GYROSCOPE THERAPEUTICS LIMITED
Reel/Frame 056613/0753 →
Priority Claims (1)
GB 1821082
· Dec 21, 2018
· national
Continuity (1)
References Cited (66)
US 20190255193A1
· Groendahl
· 2019
[cited by examiner]
US 20210338838A1
· Hageman
· 2021
[cited by examiner]
WO WO2014194213A1
· 2014
[cited by applicant]
WO WO2015055991A1
· 2015
[cited by applicant]
WO WO2017053732A2
· 2017
[cited by applicant]
WO WO2017072515A1
· 2017
[cited by applicant]
WO WO2017194912A1
· 2017
[cited by applicant]
WO WO2018170152A1
· 2018
[cited by applicant]
WO 2018224663A1
· 2018
[cited by applicant]
WO WO2019138137A1
· 2019
[cited by applicant]
Parret et al. “Critical reflections on synthetic gene design for recombinant protein expression.” Current Opinion in Structural Biology 38 (2016): 155-162 (Year: 2016).
[cited by examiner]
Milker et al. “Kinetic modeling of an enzymatic redox cascade in vivo reveals cofactor-caused bottlenecks.” ChemCatChem 9.17 (2017): 3420-7 (Year: 2017).
[cited by examiner]
Ausubel et al., 1999, Short Protocols in Molecular Biology, Ch. 18.
[cited by applicant]
Ausubel et al., 1995, Short Protocols in Molecular Biology, Ch. 9, 13, 16.
[cited by applicant]
Gait, M.J., 1984, “Oligonucleotide Synthesis: A Practical Approach” IRL Press.
[cited by applicant]
Peden et al., 2011, “Ab-Externo AAV-Mediated Gene Delivery to the Suprachoroidal Space Using a 250 Micron Flexible Microcatheter,” PLoS One 6(2):e17140.
[cited by applicant]
Skerka et al., 2007, “Defective complement control of Factor H (Y402H) and FHL-1 in age-related macular degeneration,” Molecular Therapy 14:316-327.
[cited by applicant]
Krilisa et al., 2018, “Dual roles of different redox forms of complement factor H in protecting against age related macular degeneration” Free Radical Biology and Medicine 129:237-246.
[cited by applicant]
Choi et al., “Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons,” Molecular Brain, vol. 7, No. 17, Mar. 11, 2014, pp. 1-10.
[cited by applicant]
Clark et al., “Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration,” J Immunol., vol. 193, No. 10, Nov. 15, 2014, pp. …
[cited by applicant]
Hellwage et al., “The human complement regulatory factor-H-like protein 1, which represents a truncated form of factor H, displays cell-attachment activity,” Biochemical Journal., vol. 326, Oct. 1997, pp. 321-327.
[cited by applicant]
Naama et al., “Prevention of immune precipitation by purified components of the altemative pathway,” Clin. exp. Immunol., vol. 60, 1985 (Accepted Oct. 31, 1984), pp. 169-177.
[cited by applicant]
Ricklin et al., “The renaissance of complement therapeutics,” Nature Reviews Nephrology, vol. 14, No. 1, 2017 (Published Jan. 2018), pp. 26-47.
[cited by applicant]
Office Action and Search Report issued May 5, 2023 in Russian application No. 2021119359, including unofficial English translation of Office Action.
[cited by applicant]
Dlin et al., 2016, “Nephropathies associated with complement system pathology,” Ros Vestn Perinatol I Pediatr 61(6):21-31.
[cited by applicant]
Allocca et al., 2007, “Novel Adno-Associated Virus Serotypes Efficiently Tranduce Murine Photoreceptors,” J. Virol., 81:11372-80.
[cited by applicant]
Altschul et al., 1990, “Basic local alignment search tool,” J Mol Biol, 215(3):403-410.
[cited by applicant]
Ausubel et al., 1995, “Current Protocols in Molecular Biology”, John Wiley & Sons, pp. iii-xxii.
[cited by applicant]
Bainbridge et al., 2008, “Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis,” N. Engl. J. Med., 358:2231-2239.
[cited by applicant]
Bressler et al., 1999, “Photodynamic Therapy of Subfoveal Choroidal Neovascularization in Age-related Macular Degeneration with Verteporfin,” Arch Ophthalmol 117: 1329-1345.
[cited by applicant]
Cai et al., 2014, “Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases,” ELIFE, 3:01911.
[cited by applicant]
Cashman et al., 2015, “Adenovirus-mediated delivery of Factor H attenuates complement C3 induced pathology in the murine retina: a potential gene therapy for age-related macular degeneration,” J. Gene Medicine, 17:229-2…
[cited by applicant]
Choi et al., 2005, “AAV Hybrid Serotypes: Improved Vectors for Gene Delivery” Current Gene Therapy, 5(3):299-310.
[cited by applicant]
Clark et al., 2015, “Role of Factor H and Related Proteins I Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeration,” J Clin Med, 4:18-31.
[cited by applicant]
Degn et al., 2011, “Disease-causing mutations in genes of the complement system,” Am J Hum Genet, 88:689-705.
[cited by applicant]
Devereux et al., 1984, “A comprehensive set of sequence analysis programs for the VAX,” Nucleic Acids Res 12(1):387-395.
[cited by applicant]
Dong et al., 1996, “Quantitative Analysis of the Packaging Capacity of Recombinant Adeno-Associated Virus,” Human Gene Therapy, 7(17):2101-2112.
[cited by applicant]
Dos Santos Coura R and Nardi N B, 2007, “The state of the art of adeno-associated virus-based vectors in gene therapy,” Virology Journal, 4:99.
[cited by applicant]
Esumi et al., 2004, “Analysis of the VMD2 Promoter and Implication of E-box Binding Factors in Its Regulation,” J. Biol. Chem., 279:19064-19073.
[cited by applicant]
Gaj et al., 2012, “Targeted gene knockout by direct delivery of zinc-finger nuclease proteins,” Nature Methods, 9(8):805-807.
[cited by applicant]
Goldberger et al., 1987, “Human Complement Factor I: Analysis of cDNA-derived Primary Structure and Assignment of its Gene to Chromosome 4,” J Biol. Chem., 262(21):10065-10071.
[cited by applicant]
Harrison R A, 1996, Purification, Assay, and Characterization of Comlement Proteins from Plasma, in : “Herzenberg L A & Weir D M (eds)” “Weir's Handbook of Experimental Immunology”, 5(75):36-37.
[cited by applicant]
Hsiung et al., 1982, “Purification of human C3b inactivator by monoclonal-antibody affinity chromatography,” Biochem J., 203:293-298.
[cited by applicant]
Kavanagh et al., 2015, “Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels,” Human Mol Genet, 24:3861-3870.
[cited by applicant]
Lachmann P J & Hobart M J, 1978, “Handbook of Experimental Imunology”, chapter 5A “Complement Technology”, 17 pages.
[cited by applicant]
Lachmann P J, 2009, “The amplification loop of the complement pathways,” Adv. Immunol., 104:115-149.
[cited by applicant]
Laughlin et al., 1979, “Spliced adenovirus-associated virus RNA,” Proc. Natl. Acad. Sci. USA, 5567-5571.
[cited by applicant]
Lilley et al., 1992, “Methods in Enzymology, vol. 211 DNA Structures”, Part A “Synthesis and Physical Analysis of DNA”, Academic Press.
[cited by applicant]
Liu D and Niu Z-X, 2009, “The structure, genetic polymorphisms, expression and biological functions of complement receptor type 1 (CR1/CD35),” Immunopharmacology and Immunotoxicology, 31:524-535.
[cited by applicant]
Maerzig et al., 2012, “Retroviral Protein Transfer: Falling Apart to Make an Impact,” Current Gene Therapy, 12:389-409.
[cited by applicant]
Mancuso et al., 2009, “Gene therapy for red-green colour blindness in adult primates,” Nature, 461(7265):784-787.
[cited by applicant]
Morgan and Harris, 2015, “Complement, a target for therapy in inflammatory and degenerative diseases,” Nature Reviews Drug Discovery, 14: 857-877.
[cited by applicant]
Naso et al., 2017, “Adeno-Associated Virus (AAV) as a Vector for Gene Therapy” BioDrugs, 31:317-334.
[cited by applicant]
Nilsson et al., 2011, “Complement factor I in health and disease” Molecular Immunology, 48:1611-1620.
[cited by applicant]
Polak, 1990, “Situ Hybridization: Principles and Practice”, Oxford University Press.
[cited by applicant]
Roe and Khan, 1996, “DNA Isolation and Sequencing: Essential Techniques”, John Wiley & Sons.
[cited by applicant]
Roversi et al., 2011, “Structural basis for complement factor I control and its disease-associated sequence polymorphisms,” Proc Nat Acad Sci, 108:12839-12844.
[cited by applicant]
Sambrook and Maniatis, 1989, “Molecular Cloning: A Laboratory Manual”, Cold Spring Harbor Laboratory Press.
[cited by applicant]
Schmidt et al., 2008, “A New Map of Glycosaminoglycan and C3b Binding Sites on Factor H,” Journal of Immunology, 181:2610-2619.
[cited by applicant]
Seddon, J.M., 2001, “Epidemiology of age-related macular degeneration.” In: Ogden, T.E., et al., eds. Ryan S.J., ed-in-chief. Retina vol. II. 3rd ed. St. Louis, Mo.: Mosby:1039-1050.
[cited by applicant]
Tatusova et al., 1999, “Blast 2 Sequences, a new tool for comparing protein and nucleotide sequences,” FEMS Microbiology Letters, 174(2):247-250.
[cited by applicant]
“UniProtKB”, Database accession No. P08603, Jan. 16, 2019.
[cited by applicant]
Wu et al., 2006, “Adeno-associated virus serotypes: vector toolkit for human gene therapy,” Molecular Therapy, 14: 316-27.
[cited by applicant]
Hallam et al., 2024, “Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degenerations,” eLife, doi.org/10.7554/eLife.99806.1, pp. 1-66.
[cited by applicant]
[cited by applicant]