US2020237799A1PendingUtilityA1
Treatment of amyotrophic lateral sclerosis (als)

Assignee: VOYAGER THERAPEUTICS INCPriority: Oct 16, 2017Filed: Oct 16, 2018Published: Jul 30, 2020
Est. expiryOct 16, 2037(~11.2 yrs left)· nominal 20-yr term from priority
Inventors:Dinah Wen-Yee Sah Holger Patzke Qingmin Chen Jenna Carroll Soper
C12N 2320/30C12N 15/85C12N 2310/14C12N 15/63C12N 2310/11C12N 15/113A61K 31/713C12N 15/86A61K 9/0085A61P 25/28A61K 48/005A61K 48/0075C12N 15/1137C12Y 115/01001A61P 21/00C12N 2330/51C12N 2750/14143
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References
Claims
Abstract

The present disclosure relates to AAVs encoding a SOD1 targeting polynucleotide which may be used to treat amyotrophic lateral sclerosis (ALS) and delivery methods for the treatment of spinal cord related disorders including ALS.
Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A method for inhibiting the expression of the superoxide dismutase 1 (SOD1) gene in a subject comprising administering to the subject a composition comprising an adeno-associated viral (AAV) vector comprising a vector genome and a capsid; wherein said vector genome comprises a modulatory polynucleotide sequence positioned between two inverted terminal repeats (ITRs) and wherein administration occurs at one or more sites via intraparenchymal delivery. 
     
     
         2 . The method of  claim 1 , wherein administration occurs at one or more sites within the spinal cord of the subject. 
     
     
         3 . The method of  claim 2 , wherein administration occurs at two sites within the spinal cord of the subject. 
     
     
         4 . The method of  claim 3 , wherein administration occurs at two sites at the cervical spinal cord region. 
     
     
         5 . The method of  claim 4 , wherein the two sites at the cervical spinal cord region are at levels C3 and C5. 
     
     
         6 . The method of  claim 4 , wherein the two sites at the cervical spinal cord region are at two levels selected from the group consisting of C1, C2, C3, C4, C5, C6, and C7. 
     
     
         7 . The method of  claim 3 , wherein administration occurs at two sites at the thoracic spinal cord region. 
     
     
         8 . The method of  claim 7 , wherein the two sites at the thoracic spinal cord region are at two levels selected from the group consisting of T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, and T12. 
     
     
         9 . The method of  claim 3 , wherein administration occurs at two sites at the lumbar spinal cord region. 
     
     
         10 . The method of  claim 9 , wherein the two sites at the lumbar spinal cord region are at two levels selected from the group consisting of L1, L2, L3, L4 and L5. 
     
     
         11 . The method of  claim 2  or  3 , wherein administration occurs at one or more sites located at one or more regions independently selected from the group consisting of cervical spinal cord, thoracic spinal cord, lumbar spinal cord, and sacral spinal cord. 
     
     
         12 . The method of  claim 11 , wherein the one or more sites are independently selected from the group consisting of C1, C2, C3, C4, C5, C6, C7, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, L1, L2, L3, L4, and L5. 
     
     
         13 . The method of  claim 11 , wherein the one or more sites are independently selected from the group consisting of C1, C2, C3, C4, C5, C6, C7, and L 1. 
     
     
         14 . A method for treating and/or ameliorating amyotrophic lateral sclerosis (ALS) in a subject, the method comprising administering to the subject in need of treatment a therapeutically effective amount of a composition comprising an adeno-associated viral (AAV) vector comprising a vector genome and a capsid; wherein said vector genome comprises a modulatory polynucleotide sequence positioned between two inverted terminal repeats (ITR) and wherein administration occurs at one or more sites by intraparenchymal delivery. 
     
     
         15 . The method of  claim 14 , wherein the expression of SOD1 is inhibited or suppressed. 
     
     
         16 . The method of any one of  claims 14 - 15 , wherein the SOD1 is wild type SOD1, mutated SOD1 with at least one mutation or both wild type SOD1 and mutated SOD1 with at least one mutation. 
     
     
         17 . The method of any one of  claims 14 - 16 , wherein the expression of SOD1 is inhibited or suppressed by about 20% to about 100%. 
     
     
         18 . The method of  claims 14 - 17 , wherein administration occurs at one or more sites within the spinal cord of the subject. 
     
     
         19 . The method of  claim 18 , wherein administration occurs at two sites within the spinal cord of the subject. 
     
     
         20 . The method of  claim 19 . wherein administration occurs at two sites at the cervical spinal cord region. 
     
     
         21 . The method of  claim 20 , wherein the two sites at the cervical spinal cord region are at levels C3 and C5. 
     
     
         22 . The method of  claim 21 , wherein the volume of administration is 5 μL to 240 μL at level C3 of the spinal cord and 5 μL to 240 μL at level C5 of the spinal cord. 
     
     
         23 . The method of  claim 21 , wherein the volume of administration is 5 μL to 60 μL at level C3 of the spinal cord and 5 μL, to 60 μL at level C5 of the spinal cord. 
     
     
         24 . The method of  claim 21 , wherein the volume of administration is 25 to 40 μL at level C3 of the spinal cord and 25 to 40 μL at level C5 of the spinal cord. 
     
     
         25 . The method of  claim 21 , wherein the dose is 1×10 10  vg to 1×10 12  vg at level C3 of the spinal cord and 1×10 10  vg to 1×10 12  vg at level C5 of the spinal cord. 
     
     
         26 . The method of  claim 21 , wherein the dose is 5×10 11  vg to 8×10 11  vg at level C. the spinal cord and 5×10 11  vg to 8×10 11  vg at level C5 of the spinal cord. 
     
     
         27 . The method of any one of  claims 22 - 24 , wherein the composition is administered at a rate of 5 μL/min. 
     
     
         28 . The method of  claim 20 , wherein the two sites at the cervical spinal cord region are at two levels selected from the group consisting of C1, C2, C3, C4, C5, C6, and C7. 
     
     
         29 . The method of  claim 19 , wherein administration occurs at two sites at the thoracic spinal cord region. 
     
     
         30 . The method of  claim 29 , wherein the two sites at the thoracic spinal cord region are at two levels selected from the group consisting of T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, and T12. 
     
     
         31 . The method of  claim 19 , wherein administration occurs at two sites at the lumbar spinal cord region. 
     
     
         32 . The method of  claim 31 , wherein the two sites at the lumbar spinal cord region are at two levels selected from the group consisting of L1, L2, L3, L4, and L5. 
     
     
         33 . The method of  claim 18  or  19 , wherein administration occurs at one or more sites located at one or more regions selected from the group consisting of cervical spinal cord, thoracic spinal cord, lumbar spinal cord, and sacral spinal cord. 
     
     
         34 . The method of  claim 33 , wherein the one or more sites are independently selected from the group consisting of C1, C2, C3, C4, C5, C6, C7, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, L1, L2, L3, L4, and L5. 
     
     
         35 . The method of  claim 33 , wherein the one or more sites are independently selected from the group consisting of C1, C2, C3, C4, C5, C6, C7. and L1. 
     
     
         36 . The method of any one of  claims 1 - 35 , wherein the modulatory polynucleotide sequence comprises a sense strand sequence and an antisense strand sequence, wherein the sense strand sequence comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 7 and the antisense strand sequence comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 8 and wherein said sense strand sequence and antisense strand sequence share a region of complementarily of at least four nucleotides in length. 
     
     
         37 . The method of  claim 36 , wherein the modulatory polynucleotide sequence comprises a sense strand sequence and an antisense strand sequence of an siRNA duplex, 
     
     
         38 . The method of  claim 37 , wherein the siRNA duplex is D-4012. 
     
     
         39 . The method of  claim 36 , wherein the region of complementarity is at least 17 nucleotides in length. 
     
     
         40 . The method of  claim 39 , wherein the region of complementarity is between 19 and 21 nucleotides in length. 
     
     
         41 . The method of  claim 39 , wherein the region of complementarity is 19 nucleotides in length. 
     
     
         42 . The method of any one of  claims 36 - 41 , wherein the sense strand sequence and the antisense strand sequence are, independently, 30 nucleotides or less. 
     
     
         43 . The method of any one of  claims 36 - 42 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 1 nucleotide. 
     
     
         44 . The method of  claim 43 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 2 nucleotides. 
     
     
         45 . The method of any one of  claims 1 - 44 , wherein the capsid is a serotype selected. from the group consisting of AAV1, AAV2, AAV2G9, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47NAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV12, AAV16.3, AAV24.1, AAV27.3, AAV42.12, AAV42-1h, AAV42-2, AAV42-3a, AAV42-3b, AAV42-4, AAV42-5a, AAV42-5b, AAV42-6b, AAV42-8, AAV42-10, AAV42-11, AAV42-12, AAV42-13, AAV42-15, AAV42-aa, AAV43-1, AAV43-12, AAV43-20, AAV43-21, AAV43-23, AAV43-25, AAV43-5, AAV44.1, AAV44.2, AAV44.5, AAV223.1, AAV223.2, AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAV1-7/rh.48, AAV1-8/rh,49, AAV2-15/rh.62, AAV2-3/rh.61, AAV2-4/rh.50, AAV2-5/rh.51, AAV3.1/hu.6, AAV3.1/hu.9, AAV3-9/fh.52, AAV3-11./rh.53, AAV4-8/r11.64, AAV4-9/rh.54, AAV4-19/rh.55, AAV5-3/rh.57, AAV5-22.1rh.58, AAV7.3/hu,7AAV16.8/hu.10, AAV16.12/hu.11, AAV29.3/bb.1, AAV29.5/bb.2, AAV106.1/hu.37, AAV114.3/hu.40, AAV127.2/hu.41, AAV127.5/hu.42, AAV128.3/hu.44, AAV130.4/hu.48, AAV145.1 /hu.53, AAV145.5/hu.54, AAV145.6/hu.55, AAV161.10/hu.60, AAV 161 .6/hu.61, AAV33.12/hu.17, AAV33.4/hu.15, AAV33.8/hu.16, AAV52/hu.19, AAV52.1/hu.20, AAV58.2/hu.25, AAVA3.3, AAVA3.4, AAVA3.5, AAVA3.7, AAVC1, AAVC2, AAVC5, AAV-DJ, AAV-DJ8, AAVF3, AAVF5, AAVH2, AAVrh.72, AAVhu.8, AAVrh.68, AAVrh.70, AAVpi.1, AAVpi.3, AAVpi.2, AAVrh.60, AAVrh.44, AAVrh.65, AAVrh.55, AAVrh.47, AAVrh.69, AAVrh.45, AAVrh.59, AAVhu.12, AAVH6, AAVLK03, AAVH-1/hu.1, AAVH-5/hu.3, AAVLG-10/rh.40, AAVLG-4/rh.38, AAVLG-9/hu.39, AAVN721-8/rh.43, AAVCh.5, AAVCh.5R1, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVCy.5R1, AAVCy.5R2, AAVCy.5R3, AAVCy.5R4, AAVcy.6, AAVhu.1, AAVhu.2, AAVhu.3, AAVhu.4, AAVhu.5, AAVhu.6, AAVhu.7, AAVhu.9, AAVhu.10, AAVhu.11, AAVhu.13, AAVhu.15, AAVhu.16, AAVhu.17, AAVhu.18, AAVhu.20, AAVhu.21, AAVhu.22, AAVhu.23.2, AAVhu.24, AAVhu.25, AAVhu.27, AAVhu.28, AAVhu.29, AAVhu.29R AAVhu.31, AAVhu.32, AAVhu.34, AAVhu.35, AAVhu.37, AAVhu.39. AAVhu.40, AAVhu.41, AAVhu.42, AAVhu.43, AAVhu.44, AAVhu.44R1, AAVhu.44R2, AAVhu.44R3, AAVhu.45, AAVhu.46, AAVhu.47, AAVhu.48, AAVhu.48R1, AAVhu.48R2, AAVhu.48R3, AAVhu.49, AAVhu.51, AAVhu.52, AAVhu.54, AAVhu.55, AAVhu.56, AAVhu.57, AAVhu.58, AAVhu.60, AAVhu.61, AAVhu.63, AAVhu.64, AAVhu.66, AAVhu.67, AAVhu.14/9, AAVhu.t19, AAVrh.2, AAVrh.2R, AAVrh.8, AAVrh.8R, AAVrh.10, AAVrh.12, AAVrh.13, AAVrh.13R, AAVrh.14, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.20, AAVrh.21, AAVrh.22, AAVrh,23, AAVrh,24, AAVrh.25, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.36, AAVrh.37, AAVrh.37R2, AAVrh.38, AAVrh.39, AAVrh.40, AAVrh.46, AAVrh.48, AAVrh.48.1, AAVrh.48.1.2NAVrh.48.2, AAVrh.49, AAVrh.51, AAVrh.52, AAVrh.53, AAVrh.54, AAVrh.56, AAVrh.57, AAVrh.58, AAVrh,61AAVrh.64, AAVrh.64R1, AAVrh.64R2, AAVrh.67, AAVrh.73, AAVrh.74, AAVrh8R, AAVrh8R A586R mutant, AAVrh8R R533A mutant, AAAV, BAAV, caprine AAV, bovine AAV, AAVhE1.1, AAVhEr1.5, AAVhER114, AAVhEr1.8, AAVhEr1.16, AAVhEr1.18, AAVhEr1.35, AAVhEr1.7, AAVhEr1.36, AAVhEr2.29AAVhEr2.4, AAVhEr2.16, AAVhEr2.30, AAVhEr2.31, AAVhEr2.36AAVhER1.23, AAVhEr3.1, AAV2.5T, AAV-PAEC, AAV-LK01, AAV-LK02, AAV-LK03, AAV-LK04, AAV-LK05, AAV-LK06, AAV-LK07, AAV-LK08, AAV-LK09, AAV-LK10, AAV-LK11, AAV-LK12, AAV-LK13, AAV-LK14, AAV-LK15, AAV-LK16, AAV-LK17, ANV-LK18NAV-LK19, AAV-PAEC2, AAV-PAEC4, AAV-PAEC6, AAV-PAEC7, AAV-PAEC8, AAV-PAEC11, AAV-PAEC12, AAV-2-pre-miRNA-101 AAV-8h, AAV-8b, AAV-h, AAV-b, AAV SM 10-2 AAV Shuffle 100-1, AAV Shuffle 100-3, AAV Shuffle 100-7, AAV Shuffle 10-2, AAV Shuffle 10-6, AAV Shuffle 10-8, AAV Shuffle 100-2, AAV SM 10-1, AAV SM 10-8 , AAV SM 100-3, AAV SM 100-10, BNP61 AAV, BNP62 AAV, BNP63 AAV, AAVrh.50, AAVrh.43, AAVrh.62, AAVrh.48, AAVhu.19, AAVhu.11, AAVhu.53, AAV4-8/fh.64, AAVLG-9/hu.39, AAV54.5/hu.23, AAV54.2/hu.22, AAV54.7/hu.24, AAV54.1/hu.21, AAV54.4R/hu.27, AAV46.2/hu.28, AAV46.6/hu.29, AAV128.1/hu.43, true type AAV (ttAAV), UPENN AAV 10, Japanese AAV 10 serotypes, AAV CBr-7.1, AAV CBr-7.10, AAV CBr-7.2, AAV CBr-7.3, AAV CBr-7.4, AAV CBr-7.5, AAV CBr-7.7, AAV CBr-7.8, AAV CBr-B7.3, AAV CBr-B7.4, AAV CBr-E1, AAV CBr-E2, AAV CBr-E3, AAV CBr-E4, AAV CBr-E5, AAV CBr-e5, AAV CBr-E6, AAV CBr-E7, AAV CBr-E8, AAV CHt-1, AAV CHt-2, AAV CHt-3, AAV CHt-6.1, AAV CHt-6.10, AAV CHt-6.5, AAV CHt-6.6AAV CHt-6.7, AAV CHt-6.8 AAV CHt-P1, AAV CHt-P2, AAV CHt-P5, AAV CHt-P6, AAV CHt-P8, AAV CHt-P9, AAV CKd-1, AAV CKd-10, AAV CKd-2, AAV CKd-3, AAV CKd-4, AAV CKd-6, AAV CKd-7, AAV CKd-8, AAV CKd-B1, AAV CKd-B2, AAV CKd-B3, AAV CKd-B4, AAV CKd-B5, AAV CKd-B6, AAV CKd-B7, AAV CKd-B8, AAV CKd-H1, AAV CKd-H2, AAV CKd-H3, AAV CKd-H4, AAV CKA-H5, AAV CKd-H6, AAV CKd-N3, AAV CKd-N4, AAV CKd-N9, AAV CLg-F1, AAV CLg-F2,NAV CLg-F3, AAV CLg-F4, AAV CLg-F5, AAV CLg-F6, AAV CLg-F7, AAV CLg-F8, AAV CLv-1, AAV CLv1-1, AAV Clv1-10, AAV CLv1-2, AAV CLv-12, AAV CLv1-3, AAV CLv-13, AAV CLv1-4, AAV Clv1-7, AAV Clv1-8, AAV Clv1-9, AAV CLv-2, AAV CLv-3, AAV CLv-4, AAV CLv-6, AAV CLv-8, AAV CLv-D1, AAV CLv-D2, AAV CLv-D3, AAV CLv-D4, AAV CLv-D5, AAV CLv-D6, AAV CLv-D7, AAV CLv-D8, AAV CLv-E1, AAV CLv-K1, AAV CLv-K3, AAV CLv-K6, AAV CLv-L4, AAV CLv-L5, AAV CLv-L6, AAV CLv-M1, AAV CLv-M11, AAV CLv-M2, AAV CLv-M5, AAV CLv-M6, AAV CLv-M7, AAV CLv-M8, AAV CLv-M9, AAV CLv-R1, AAV CLv-R2, AAV CLv-R3, AAV CLv-R4, AAV CLv-R5, AAV CLv-R6, AAV CLv-R7, AAV CLv-R8, AAV CLv-R9, AAV CSp-1, AAV CSp-10, AAV CSp-11, AAV CSp-2, AAV CSp-3, AAV CSp-4, AAV CSp-6, AAV CSp-7, AAV CSp-8, AAV CSp-8.10, AAV CSp-8.2, AAV CSp-8.4, AAV CSp-8.5, AAV CSp-8.6, AAV CSp-8.7, AAV CSp-8.8, AAV CSp-8.9, AAV CSp-9, AAV.hu.48R3, AAV,VR-355, AAV3B, AAV4, AAV5, AAVF1/HSC1, AAVF11/HSC11, AAVF12/HSC12, AAVF13/HISC13, AAVF14/HSC14, AAVF15/HSC15, AAVF16/HSC16, AAVF17/HSC17, AAVF2/HSC2, AAVF3/HSC3, AAVF4/HSC4, AAVF5/HSC5, AAVF6/HSC6, AAVF7/HSC7, AAVF8/HSC8, AAVF9/HSC9, AAV-PHP.B, AAV-PHP.A, G2B-26, G2B-13, TH1.1-32, TH1.1-35, AAVPHP.B2, AAVPHP.B3, AAVPHP.N/PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, A.AVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHIP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S/G2A12, AAVG2A15/G2A3, AAVG2B4, AAVG2B5 and variants thereof. 
     
     
         46 . The method of  claim 45 , wherein the capsid is AAVrh.10 serotype or a variant thereof. 
     
     
         47 . The method of any one of  claims 1 - 46 , wherein the AAV vector comprises a promoter, and wherein the promoter is H1.
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