Granted Patent
B2
US 12,516,301 · App. 17/606,890 · Granted Jan 6, 2026
Optimized SUMF1 genes and expression cassettes and their use
C12N9/0051A61K38/44A61K48/005A61P3/00C12N15/86C12Y108/03C12N2710/10343C12N2710/16143C12N2750/14143C12N2750/14171C12N2800/22
View Patent ↗
Loading inventors, assignments & file history…
Abstract
This invention relates to polynucleotides comprising optimized SUMF1 open reading frame (ORF) sequences, vectors comprising the same, and methods of using the same for deliver) of the ORF to a cell or a subject and to treat disorders associated with aberrant expression of a SUMF1 gene or aberrant activity of a SUMF1 gene product in the subject, such as SUMF1 disease.
Claims (19)
1. A polynucleotide comprising a human SUMF1 open reading frame, wherein the human SUMF1 open reading frame is codon-optimized for expression in a human cell and comprises the nucleotide sequence of SEQ ID NO: 1 or a nucleotide sequence having at least about 90% identity thereto.
2. An expression cassette comprising the polynucleotide of claim 1 .
3. The expression cassette of claim 2 , wherein the human SUMF1 open reading frame is operably linked to a promoter, an enhancer and/or a polyadenylation signal.
4. The expression cassette of claim 3 , wherein the promoter is a chicken beta actin promoter, wherein the polyadenylation signal is a simian virus 40 (SV40) polyadenylation signal, and/or wherein the enhancer is a cytomegalovirus (CMV) enhancer.
5. The expression cassette of claim 3 , further comprising at least one adeno-associated virus (AAV) inverted terminal repeat (ITR).
6. The expression cassette of claim 5 , wherein the expression cassette comprises two AAV ITRs.
7. The expression cassette of claim 6 , wherein one of the two AAV ITRs is a modified ITR.
8. The expression cassette of claim 6 , wherein the expression cassette is a self-complementary AAV genome.
9. The expression cassette of claim 2 , wherein the expression cassette comprises a promoter, the human SUMF1 open reading frame, and a polyadenylation site.
10. The expression cassette of claim 9 , wherein the expression cassette comprises an AAV ITR, a promoter, the human SUMF1 open reading frame, a polyadenylation site, and an AAV ITR.
11. The expression cassette of claim 10 , wherein the expression cassette comprises an AAV ITR, a CMV enhancer, a chicken beta actin promoter, the human SUMF1 open reading frame, an SV40 polyadenylation site, and an AAV ITR.
12. The expression cassette of claim 11 , wherein the expression cassette comprises an AAV2 ITR, a CMV enhancer, a chicken beta actin promoter, the human SUMF1 open reading frame, an SV40 polyadenylation site, and an AAV2 ITR.
13. The expression cassette of claim 12 , comprising the nucleotide sequence of SEQ ID NO: 10 or a sequence at least about 90% identical thereto.
14. A vector comprising the polynucleotide of claim 1 .
15. The vector of claim 14 , wherein the vector is an AAV vector.
16. A pharmaceutical composition comprising the polynucleotide of claim 1 in a pharmaceutically acceptable carrier.
17. A method of expressing a SUMF1 open reading frame in a subject, comprising delivering to the subject the pharmaceutical composition of claim 16 , thereby expressing the SUMF1 open reading frame in the subject.
18. A method of treating a disorder associated with aberrant expression of a SUMF1 gene or aberrant activity of a SUMF1 gene product in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 16 , such that the SUMF1 open reading frame is expressed in the subject.
19. A method of treating multiple sulfatase deficiency (MSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 16 , such that the SUMF1 open reading frame is expressed in the subject.
Assignments (4)
RELEASE OF SECURITY INTEREST
Recorded Feb 13, 2026
From: TRINITY CAPITAL INC.
To: TAYSHA GENE THERAPIES, INC.
Reel/Frame 074858/0456 →
SECURITY INTEREST
Recorded Aug 8, 2025
From: TAYSHA GENE THERAPIES, INC.
To: TRINITY CAPITAL, INC., AS ADMINISTRATIVE AGENT AND COLLATERAL AGENT
Reel/Frame 071976/0658 →
SECURITY INTEREST
Recorded Jul 30, 2025
From: TAYSHA GENE THERAPIES, INC.
To: TRINITY CAPITAL INC.
Reel/Frame 071886/0097 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 19, 2021
From: GRAY, STEVEN JAMES; BAILEY, RACHEL
To: THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Reel/Frame 058169/0261 →
Continuity (2)
Provisional Application
62840114
· Apr 29, 2019
References Cited (95)
US 4501729A
· Boucher et al.
· 1985
[cited by applicant]
US 5399346A
· Anderson et al.
· 1995
[cited by applicant]
US 5478745A
· Samulski et al.
· 1995
[cited by applicant]
US 6040183A
· Ferrari et al.
· 2000
[cited by applicant]
US 6093570A
· Ferrari et al.
· 2000
[cited by applicant]
US 6156303A
· Russell et al.
· 2000
[cited by applicant]
US 7201898B2
· Monahan et al.
· 2007
[cited by applicant]
US 9636370B2
· McCown et al.
· 2017
[cited by applicant]
US 20170191041A1
· Radin
· 2017
[cited by applicant]
WO 9811244A2
· 1998
[cited by applicant]
WO 9961601A2
· 1999
[cited by applicant]
WO 0017377A2
· 2000
[cited by applicant]
WO 0028004A1
· 2000
[cited by applicant]
WO 0028061A2
· 2000
[cited by applicant]
WO 0191803A2
· 2001
[cited by applicant]
WO 0192551A2
· 2001
[cited by applicant]
WO 2014136065A2
· 2014
[cited by applicant]
WO 2018093925A1
· 2018
[cited by applicant]
Laoharawee et al. (2017) “Prevention of neurocognitive deficiency in mucopolysaccharidosis type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer” Human gene therapy, 28(8), 626…
[cited by examiner]
Mccarty, D. M. (2008) “Self-complementary AAV vectors; advances and applications” Molecular therapy, 16(10), 1648-1656. (Year: 2008).
[cited by examiner]
Choi et al. (2014) “Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons” Molecular brain, 7:17, 10 pages. (Year: 2014).
[cited by examiner]
Ahrens-Nicklas et al. “Complex care of individuals with Multiple Sulfatase Deficiency: clinical cases and consensus statement” Molecular Genetics and Metabolism, 123(3):337-346 (2018).
[cited by applicant]
Carlson et al. “Function and Structure of a Prokaryotic Formylglycine-generating Enzyme” Journal of Biological Chemistry, 283(29):20117-20125 (2008).
[cited by applicant]
Chao et al. “Several Log Increase in Therapeutic Transgene Delivery by Distinct Adeno-Associated Viral Serotype Vectors” Molecular Therapy, 2(6):619-623 (2000).
[cited by applicant]
Conway et al. “High-titer recombinant adeno-associated virus production utilizing a recombinant herpes simplex virus ype I vector expressing AAV-2 Rep and Cap” Gene Therapy, 6:986-993 (1999).
[cited by applicant]
Cosma et al. “The Multiple Sulfatase Deficiency Gene Encodes an Essential and Limiting Factor for the Activity of Sulfatases” Cell, 113:445-456 (2003).
[cited by applicant]
Dierks et al. “Molecular Basis for Multiple Sulfatase Deficiency and Mechanism for Formylglycine Generation of the Human Formylglycine-Generating Enzyme” Cell, 121(4):541-552 (2005).
[cited by applicant]
Dierks et al. “Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease—Lysosomal storage disorders caused by defects of non-lysosomal proteins” Biochimica et Biophysica Acta, 1…
[cited by applicant]
Dierks et al. “Multiple Sulfatase Deficiency Is Caused by Mutations in the Gene Encoding the Human C(alpha)-Formylglycine Generating Enzyme” Cell, 113(4):435-444 (2003).
[cited by applicant]
Eto et al. “Pathochemistry, Pathogenesis and Enzyme Replacement in Multiple-Sulfatase Deficiency” Enzyme, 38(1-4):273-279 (1987) (Abstract only).
[cited by applicant]
Federici et al. “Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs” Gene Therapy, 19(8):852-859 (2011).
[cited by applicant]
Feng et al. “Progressive Sequence Alignment as a Prerequisite to Correct Phylogenetic Trees” Journal of Molecular Evolution, 25:351-360 (1987).
[cited by applicant]
Gao et al. “Clades of Adeno-Associated Viruses are Widely Disseminated in Human Tissues” Journal of Virology, 78(12):6381-6388 (2004).
[cited by applicant]
Garavelli et al. “Multiple sulfatase deficiency with neonatal manifestation” Italian Journal of Pediatrics, 40:86 (2014).
[cited by applicant]
GenBank Accession No. AF028704 “Adeno-associated virus 6, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Jan. 12, 1998).
[cited by applicant]
GenBank Accession No. AF028705 “Adeno-associated virus 3B, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Jan. 12, 1998).
[cited by applicant]
GenBank Accession No. AF043303 “Adeno-associated virus 2, complete genome” www.ncbi.nlm.nih.gov (4 pages) (May 20, 2010).
[cited by applicant]
GenBank Accession No. AF063497 “Adeno-associated virus 1, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Apr. 27, 1999).
[cited by applicant]
GenBank Accession No. AF288061 “Hamster parvovirus 5′ terminal hairpin gene sequence” www.ncbi.nlm.nih.gov (1 bage) (Apr. 13, 2001).
[cited by applicant]
GenBank Accession No. AF513851 “Adeno-associated virus 7 nonstructural protein and capsid protein genes, complete cds” www.ncbi.nlm.nih.gov (3 pages) (Sep. 5, 2002).
[cited by applicant]
GenBank Accession No. AF513852 “Adeno-associated virus 8 nonstructural protein and capsid protein genes, complete cds” www.ncbi.nlm.nih.gov (3 pages) (Sep. 5, 2002).
[cited by applicant]
GenBank Accession No. AH009962 “Hamster parvovirus” www.ncbi.nlm.nih.gov (2 pages) (Aug. 25, 2016).
[cited by applicant]
GenBank Accession No. AX753250 “Sequence 5 from Patent EP1310571” www.ncbi.nlm.nih.gov (2 pages) (Jun. 23, 2003).
[cited by applicant]
GenBank Accession No. AY028223 “B19 virus isolate patient_A.1.1 genomic sequence” www.ncbi.nlm.nih.gov (1 bage) (Apr. 16, 2001).
[cited by applicant]
GenBank Accession No. AY028226 “B19 virus isolate patient_A.2.1 genomic sequence” www.ncbi.nlm.nih.gov (1 bage) (Apr. 16, 2001).
[cited by applicant]
GenBank Accession No. AY530579 “Adeno-associated virus 9 isolate hu.14 capsid protein VP1 (cap) gene, complete cds” www.ncbi.nlm.nih.gov (2 pages) (Jun. 24, 2004).
[cited by applicant]
GenBank Accession No. AY631966 “Adeno-associated virus 11 nonstructural protein and capsid protein genes, complete cds” www.ncbi.nlm.nih.gov (3 pages) (Nov. 30, 2004).
[cited by applicant]
GenBank Accession No. EU285562 “Adeno-associated virus 13 nonstructural protein and capsid protein genes, complete cds” www.ncbi.nlm.nih.gov (3 pages) (Sep. 23, 2008).
[cited by applicant]
GenBank Accession No. J01901 “Adeno-associated virus 2, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Apr. 27, 1993).
[cited by applicant]
GenBank Accession No. J02275 “Minute virus of mice, complete genome” www.ncbi.nlm.nih.gov (5 pages) (May 22, 1995).
[cited by applicant]
GenBank Accession No. NC_000883 “Human parvovirus B19, complete genome” www.ncbi.nlm.nih.gov (4 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001358 “Parvovirus H1, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Feb. 10, 2015).
[cited by applicant]
GenBank Accession No. NC_001401 “Adeno-associated virus—2, complete genome” www.ncbi.nlm.nih.gov (6 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001510 “Minute virus of mice, complete genome” www.ncbi.nlm.nih.gov (5 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001540 “Bovine parvovirus, complete genome” www.ncbi.nlm.nih.gov (4 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001701 “Goose parvovirus, complete genome” www.ncbi.nlm.nih.gov (4 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001729 “Adeno-associated virus—3, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001829 “Adeno-associated virus—4, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_001862 “Adeno-associated virus 6, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Jan. 12, 2004).
[cited by applicant]
GenBank Accession No. NC_001863 “Adeno-associated virus 3B, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Jan. 12, 2004).
[cited by applicant]
GenBank Accession No. NC_002077 “Adeno-associated virus—1, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_006152 “Adeno-associated virus 5, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. NC_006261 “Adeno-associated virus—8, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Aug. 13, 2018).
[cited by applicant]
GenBank Accession No. U89790 “Adeno-associated virus 4, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Aug. 21, 1997).
[cited by applicant]
GenBank Accession No. X01457 “Parvovirus h-1, complete genome” www.ncbi.nlm.nih.gov (3 pages) (Apr. 18, 2005).
[cited by applicant]
Gray et al. “Optimizing Promoters for Recombinant Adeno-Associated Virus-Mediated Gene Expression in the Peripheral and Central Nervous System Using Self-Complementary Vectors” Human Gene Therapy, 22(9):1134-1153 (2011).
[cited by applicant]
Gray et al. “Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman Primates” Molecular Therapy, 19(6):1058-1069 (2011).
[cited by applicant]
International Preliminary Report on Patentability corresponding to International Patent Application No. PCT/US2020/030236 (7 pages) (dated Nov. 11, 2021).
[cited by applicant]
Jaszczuk et al. “Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease” Molecular Genetics and Metabolism, 121(3):252-258…
[cited by applicant]
Landgrebe et al. “The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family which is conserved from pro-to eukaryotes” Gene, 316:47-56 (2003).
[cited by applicant]
Margolskee, R. F. “Epstein-Barr Virus Based Expression Vectors” Current Topics in Microbiology and Immunology, 158:67-95 (1992).
[cited by applicant]
McCarty et al. “Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo” Gene Therapy, 10:2112-2118 (2003).
[cited by applicant]
McCarty et al. “Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis” Gene Therapy, 8:1248-1254 (2001).
[cited by applicant]
Muzyczka, N. “Use of Adeno-Associated Virus as a General Transduction Vector for Mammalian Cells” Current Topics in Microbiology and Immunology, 158:97-98 (1992).
[cited by applicant]
Nur et al. “Neonatal multiple sulfatase deficiency with a novel mutation and review of the literature” The Turkish Journal of Pediatrics, 56(4):418-422 (2014).
[cited by applicant]
Palombo et al. “Site-Specific Integration in Mammalian Cells Mediated by a New Hybrid Baculovirus-Adeno-Associated Virus Vector” Journal of Virology, 72(6):5025-5034 (1998).
[cited by applicant]
Preusser-Kunze et al. “Molecular characterization of the human Calpha-formylglycine-generating enzyme” The Journal of Biological Chemistry, 280(15):14900-14910 (2005).
[cited by applicant]
Sabourdy et al. “Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency” Orphanet Journal of Rare Diseases, 10:31 (2015).
[cited by applicant]
Sardiello et al. “Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship” Human Molecular Genetics, 14(21):3203-3217 (2005).
[cited by applicant]
Schlotawa et al. “Molecular Analysis of SUMF1 Mutations: Stability and Residual Activity of Mutant Formylglycine-Generating Enzyme Determine Disease Severity in Multiple Sulfatase Deficiency” Human Mutation, 29(1):205 (…
[cited by applicant]
Schlotawa et al. “SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency” European Journal of Human Genetics, 19(3):253-261 (2011).
[cited by applicant]
Schmidt et al. “A Novel Amino Acid Modification in Sulfatases That Is Defective in Multiple Sulfatase Deficiency” Cell, 82(2):271-278 (1995).
[cited by applicant]
Settembre et al. “Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency” Proceedings of the National Academy of Sciences, 104(11):4506-4511 (2007).
[cited by applicant]
Spampanato et al. “Efficacy of a Combined Intracerebral and Systemic Gene Delivery Approach for the Treatment of a Severe Lysosomal Storage Disorder” Molecular Therapy, 19(5):860-869 (2011).
[cited by applicant]
Urabe et al. “Insect Cells as a Factory to Produce Adeno-Associated Virus Type 2 Vectors” Human Gene Therapy, 13:1935-1943 (2002).
[cited by applicant]
Zhang et al. “Recombinant adenovirus expressing adeno-associated virus cap and rep proteins supports production of hightiter recombinant adeno-associated virus” Gene Therapy, 8:704-712 (2001).
[cited by applicant]
Zolotukhin et al. “Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield” Gene Therapy, 6:973-985 (1999).
[cited by applicant]
Fraldi et al. “SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies” Biochemical Journal, 403:305-312 (2007).
[cited by applicant]
International Search Report and the Written Opinion of the International Searching Authority corresponding to International Patent Application No. PCT/US2020/030236 (13 pages) (mailed Aug. 12, 2020).
[cited by applicant]
Bailey et al. “Development of scAAV9/SUMF1 gene therapy for multiple sulfatase delivery” Molecular Genetics and Metabolism, 126(2):S27 (2019).
[cited by applicant]
Extended European Search Report corresponding to European Patent Application No. 20798551.6 (11 pages) (dated Dec. 22, 2022).
[cited by applicant]
Laoharawee et al. “Prevention of Neurocognitive Deficiency in Mucopolysaccharidosis Type II Mice by Central Nervous System-Directed, AAV9-Mediated Iduronate Sulfatase Gene Transfer” Human Gene Therapy, 28(8):626-638 (20…
[cited by applicant]