IP Library › Granted Patent US 12,257,322
Granted Patent B2
US 12,257,322 · App. 18/052,082 · Granted Mar 25, 2025

Optimized CLN1 genes and expression cassettes and their use

Inventor: Steven Gray (Southlake, TX)
Assignee: The University of North Carolina at Chapel Hill
A61K48/0066C12N15/86C12N2750/14143C12N2750/14145C12N2830/002
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Quick Facts
Patent No.
US 12,257,322
App. No.
18/052,082
Granted
Mar 25, 2025
Kind
B2
Abstract

This invention relates to polynucleotides comprising a nucleotide sequence encoding a PPT1 polypeptide or a fragment thereof, vectors (viral or non-viral vectors) comprising the same, and methods of using the same for delivery of the open reading frame to a cell or a subject and to treat infantile neuronal lipofuscinosis (infantile Batten disease). The polynucleotides comprise an optimized CLN1 open reading frame.

Claims (22)

1. A method of expressing a Ceroid-Lipofuscinosis, Neuronal 1 (CLN1) open reading frame in a cell, comprising contacting the cell with a polynucleotide comprising a human CLN1 open reading frame, wherein the human CLN1 open reading frame comprises the nucleotide sequence of SEQ ID NO: 1 or its complement, thereby expressing the CLNI open reading frame in the cell.

2. A method of expressing a CLN1 open reading frame in a subject, comprising delivering to the subject a polynucleotide comprising a human CLN1 open reading frame, wherein the human CLNI open reading frame comprises the nucleotide sequence of SEQ ID NO: 1 or its complement, thereby expressing the CLN1 open reading frame in the subject.

3. A method of treating a disorder associated with aberrant expression of a CLN1 gene or aberrant activity of a CLNI gene product in a subject in need thereof, comprising delivering to the subject a therapeutically effective amount of a polynucleotide comprising a human CLNI open reading frame, wherein the human CLNI open reading frame comprises the nucleotide sequence of SEQ ID NO: 1 or its complement, thereby treating the disorder associated with aberrant expression of the CLNI gene in the subject.

4. The method of claim 3 , wherein the disorder associated with expression of the CLN1 gene is infantile, late-infantile, juvenile, or adult-onset neuronal ceroid lipofuscinosis.

5. The method of claim 3 , wherein the polynucleotide is delivered to the nervous system of the subject.

6. The method of claim 3 , wherein the polynucleotide is delivered by intrathecal, intracerebral, intraventricular, intranasal, intra-aural, intra-ocular, or peri-ocular delivery, or any combination thereof.

7. The method of claim 3 , wherein the polynucleotide, expression cassette, vector, and/or transformed cell is delivered intravenously.

8. The method of claim 3 , wherein the polynucleotide is operably linked to a promoter, optionally a chicken beta actin promoter.

9. The method of claim 3 , wherein the polynucleotide is operably linked to an enhancer, optionally a cytomegalovirus enhancer.

10. The method of claim 3 , wherein the polynucleotide is operably linked to an intron, optionally a hybrid/modified mouse parvovirus (MVM) intron.

11. The method of claim 3 , wherein the polynucleotide is operably linked to a polyadenylation signal, optionally a bovine growth hormone polyadenylation signal.

12. The method of claim 3 , wherein the expression cassette comprises at least one adeno-associated virus (AAV) inverted terminal repeat (ITR).

13. The method of claim 3 , wherein the expression cassette is a self-complementary AAV genome.

14. The method of claim 3 , wherein the expression cassette comprises an enhancer, a promoter, an intron, a human CLN1 open reading frame, and a polyadenylation site.

15. The method of claim 3 , wherein the expression cassette comprises a mutant AAV ITR, a CMV enhancer, a chicken beta actin promoter, a hybrid/modified MVM intron, a human CLN1 open reading frame, a bovine growth hormone polyadenylation site, and a wild-type AAV ITR.

16. The method of claim 15 , wherein the expression cassette comprises the nucleotide sequence of SEQ ID NO: 7 or a sequence at least about 90% identical thereto.

17. The method of claim 3 , wherein the vector is a viral vector.

18. The method of claim 17 , wherein the vector is an AAV vector.

19. The method of claim 18 , wherein the AAV vector is an AAV9 vector.

20. The method of claim 19 , wherein the AAV vector is a self-complementary AAV9 vector.

21. The method of claim 3 , wherein the polynucleotide is delivered intravitreally.

22. The method of claim 3 , wherein a disorder associated with aberrant expression of a CLNI gene or aberrant activity of a CLNI gene product is infantile neuronal ceroid lipofuscinosis.

Assignments (3)
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 →
Continuity (3)
Division 16305337
Provisional Application 62349411 · Jun 13, 2016
Related Publication 20230372544A1 · Nov 23, 2023
References Cited (51)
US 6582692B1 · Podsakoff et al. · 2003 [cited by applicant]
US 7442372B2 · Kakkis · 2008 [cited by applicant]
US 7906111B2 · Wilson et al. · 2011 [cited by applicant]
US 8242086B2 · Boustany · 2012 [cited by applicant]
US 9926574B2 · Barkats · 2018 [cited by applicant]
US 10208318B2 · Barkats · 2019 [cited by applicant]
US 10301648B2 · Vandenberghe et al. · 2019 [cited by applicant]
US 20030083299A1 · Ferguson · 2003 [cited by applicant]
US 20150313863A1 · Kalipada · 2015 [cited by applicant]
AU 2014337783A1 · 2016 [cited by applicant]
EP 1620133A1 · 2006 [cited by applicant]
RU 2330861C2 · 2008 [cited by applicant]
WO 2001092551A1 · 2001 [cited by applicant]
“Decision to Grant corresponding to Russian Application No. 2018145010 issued Nov. 22, 2021”. [cited by applicant]
“Examination Report corresponding to European Application No. 17813890.5 dated Dec. 10, 2020”. [cited by applicant]
“Examination Report corresponding to European Application No. 17813890.5 dated Mar. 11, 2022”. [cited by applicant]
“Extended European Search Report corresponding to European Application No. 17813890.5 dated Jan. 7, 2020”. [cited by applicant]
“Gray, “Gene therapy for INCL”, Workshop, Batten Disease: 2016 Update of Translational Research for Management of INCL/LINCL, Bethesda, MD, Mar. 30-31, 2016”. [cited by applicant]
“International Preliminary Report on Patentability corresponding to International Application No. PCT/US2017/037118 mailed Dec. 27, 2018”. [cited by applicant]
“International Search Report and Written Opinion corresponding to International Application No. PCT/US2017/037118 mailed Aug. 31, 2017”. [cited by applicant]
“Office Action corresponding to Japanese Application No. 2018-564943 mailed Jun. 28, 2021”. [cited by applicant]
“Office Action corresponding to Australian Application No. 2017284198 dated Sep. 29, 2022”. [cited by applicant]
“Office Action corresponding to Brazilian Application No. 112018075692-0 issued Oct. 11, 2022”. [cited by applicant]
“Office Action corresponding to Chinese Application No. 201 7800367811 issued Apr. 6, 2021”. [cited by applicant]
“Office Action corresponding to Chinese Application No. 201780036781.1 issued Jan. 5, 2022”. [cited by applicant]
“Office Action corresponding to Israeli Application No. 263,009 issued Oct. 21, 2021”. [cited by applicant]
“Office Action corresponding to Japanese Application No. 2018-564943 mailed Mar. 3, 2022”. [cited by applicant]
“Office Action corresponding to Korean Application No. 10-2018-7035890 issued Jul. 20, 2022”. [cited by applicant]
“Office Action corresponding to Mexican Application No. MX/a/2018/015461 issued Jul. 1, 2022”. [cited by applicant]
“Office Action corresponding to Russian Application No. 2018145010 issued Dec. 23, 2020”. [cited by applicant]
Asanov, A. Yu, et al., “Fundamentals of genetics and hereditary developmental disorders in children”, Moscow: Publishing Center “Academy”, 2003, 214 pages. [cited by applicant]
Bosch , et al., ““Long-Term and Significant Correction of Brain Lesions in Adult Mucopolysaccharidosis Type VII Mice Using Recombinant AAV Vectors”, Molecular Therapy 1(1):63-70 (2000)”. [cited by applicant]
Brown, Harrison C, et al., “Tissue Directed Transgene Engineering for AAV and Lentivector Gene Therapy Approaches”, Molecular Therapy 24(Suppl. 1):S287 Abstract No. 728 (May 2016). [cited by applicant]
Bulatnikova, M A., et al., “Clinical observation of 1st type neuronal lipofuscinosis (Santavuori-Haltia syndrome)”, Kliniko-laboratornyij konsilium, 2012, No. 2(42), pp. 48-52 (see the abstract). [cited by applicant]
Büning , et al., “”Recent developments in adeno-associated virus vector technology“, J Gene Med 10:717-733 (2008)”. [cited by applicant]
Dennis, M. B., “Welfare issues of genetically modified animals”, ILAR Journal, 2002, vol. 43, Issue 2, pp. 100-109. [cited by applicant]
Griffey , et al., “”Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis“, Neurobiology of Dise… [cited by applicant]
Griffey , et al., ““CNS-Directed AAV2-Mediated Gene Therapy Ameliorates Functional Deficits in a Murine Model of Infantile Neuronal Ceroid Lipofuscinosis”, Molecular Therapy 13(3):538-547 (2006)”. [cited by applicant]
Kollmann , et al., ““Cell biology and function of neuronal ceroid lipofuscinosis-related proteins”, Biochimica et Biophysica Acta 1832:1866-1881 (2013)”. [cited by applicant]
Mauro, Vincent P., et al., “A critical analysis of codon optimization in human therapeutics”, Trends in Molecular Medicine, 20(11), 2014, 604-613. [cited by applicant]
Michelfelder , et al., ““Peptide Ligands Incorporated into the Threefold Spike Capsid Domain to Re-Direct Gene Transduction of AAV8 and AAV9 In Vivo”, PLOS ONE 6(8):e23101 (2011) 11 pages”. [cited by applicant]
Parret, Annabel Ha, et al., “Critical Reflections on synthetic gene design for recombinant protein expression”, Current Opinion in Structural Biology 38:155-162 (2016). [cited by applicant]
Rozenberg, Alejandra J., et al., “362. Translatable Gene Therapy for Infantile Neuronal Lipofuscinosis”, Molecular Therapy 24 (May 2016):S145. [cited by applicant]
Sen , et al., ““Targeted Modifications in Adeno-Associated Virus Serotype 8 Capsid Improves Its Hepatic Gene Transfer Efficiency In Vivo”, Human Gene Therapy Methods 24:104-116 (2013)”. [cited by applicant]
Vance, Melisa , et al., “AAV gene therapy for MPS1-associated corneal blindness”, Scientific Reports, 6(1) (Feb. 22, 2016), 2016, 1-10. [cited by applicant]
Xiao, Weidong , et al., “Gene therapy vectors based on adeno-associated virus type 1”, Journal of Virology, 73(5), 1999, 3994-4003. [cited by applicant]
Zhou, H. , et al., “Developing tTA transgenic rats for inducible and reversible gene expression”, International Journal of Biological Sciences, 2009, vol. 5, Issue 2, pp. 171-181. [cited by applicant]
“Office Action corresponding to Korean Application No. 10-2018-7035890 issued Mar. 29, 2023”. [cited by applicant]
“Examination Report corresponding to European Application No. 17813890.5 dated Jul. 16, 2024”. [cited by applicant]
Gessler, Dominic J, et al., “Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease”, JCI Insight. 2(3):e90807 (Feb. 9, 2017) 17 pages. [cited by applicant]
“Office Action corresponding to Brazilian Application No. 112018075692-0 issued Nov. 4, 2024”. [cited by applicant]