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Aav viral vectors and uses thereof

A virus vector, intrathecal administration technology, applied in the field of virus particle composition, can solve problems such as lengthy induction period

Pending Publication Date: 2021-08-06
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical studies have demonstrated some degree of promise for improved motor function; however, treatment must be administered indefinitely on a quarterly basis via intrathecal injection, requires a lengthy induction period before effectiveness is achieved, and has safety concerns that require clinical monitoring sexual considerations

Method used

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  • Aav viral vectors and uses thereof
  • Aav viral vectors and uses thereof
  • Aav viral vectors and uses thereof

Examples

Experimental program
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preparation example Construction

[0139] The rAAV viral vectors disclosed herein can be prepared according to methods of preparation and purification known in the art. In some embodiments, the purpose of the purification method is to remove contaminants from the host cells and chemicals added during collection of the viral vector. In some embodiments, the methods disclosed in PCT / US2018 / 058744, which is incorporated herein by reference in its entirety, are used. In some embodiments, these methods use about 1×10 13 vg / mL and 1×10 15 Between vg / mL, such as about 1-8×10 13 Concentrations between vg / mL yield rAAV viral vectors. In some embodiments, these methods use about 1.0×10 13 vg-9.9×10 14 Doses (eg, unit doses) of vg yield rAAV viral vectors. In some embodiments, these methods use about 1.0×10 13 vg-5.0×10 14 Doses (eg, unit doses) of vg yield rAAV viral vectors. In some embodiments, these methods use about 5.0×10 13 vg-3.0×10 14 Doses (eg, unit doses) of vg yield rAAV viral vectors. In some embo...

example

[0172] preclinical evaluation

[0173] The SMNΔ7 mouse is a suitable model for studying gene transfer. Butchbach et al., "Abnormal motorphenotype in the SMNΔ7 mouse model of spinal muscular atrophy [SMNΔ7 mouse spinal muscular atrophy model abnormal motor phenotype]" Neurobiology of disease [disease of neurobiology], 27 (2): 207 -19. 5 x 10 of scAAV9.CB.SMN 11 Injection of individual viral genomes into the facial vein of 1-day-old mice rescued the SMNΔ7 mouse model. Foust et al., "Rescue of the spinal muscular atrophy phenotypein a mouse model by early postnatal delivery of SMN," Nature biotechnology, 28(3):271-4. Approximately 42 ± 2% of lumbar spinal motoneurons were transduced in scAAV9.CB.SMN-treated mice. SMN levels were also increased in the brain, spinal cord and muscle of scAAV9.CB.SMN-treated animals compared to untreated SMA mice (albeit lower than WT controls). The ability of scAAV9.CB.SMN- or scAAV9.CB.GFP-treated SMA animals to return to normal posture was a...

example 1

[0186] Example 1 - Clinical Trial Protocol

[0187] Phase 1, open-label, single-dose clinical trial in infants and children with a genetic diagnosis of SMA, biallelic deletion of SMN1, and 3 copies of SMN2 (no genetic modifiers), at Able to sit but not stand or walk on study entry. Patients received up to three (3) potentially therapeutic doses of AVXS-101 in the dose comparison safety study, as described below. Patients were divided into two groups, age ≥6 months and 6 months and 24 and <60 months were enrolled.

[0188] The first group enrolled three (3) patients aged ≥6 months and 13 Administration of vg of AVXS-101 (dose A). There was an interval of at least four (4) weeks between dosing for each patient within the cohort. Investigators reported to the Data Safety Monitoring Board (DSMB) all AEs of grade III or higher that were likely, probable, or definitively related to the study reagents within 48 hours before proceeding with enrollment. After enrolling the first th...

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Abstract

Disclosed herein are compositions comprising AAV9 viral vectors and methods of using them to treat SMA patients, e.g., Type II and Type III Spinal Muscular Atrophy (SMA) patients.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 773,894, filed November 30, 2018, and U.S. Provisional Patent Application No. 62 / 835,242, filed April 17, 2019. The contents of these applications are incorporated herein by reference in their entirety. [0003] sequence listing [0004] This application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy was created on November 12, 2019, with the name 14452_0025-00304_SL.txt and a size of 14,833 bytes. technical field [0005] The present disclosure relates to compositions and uses of viral particles. Background technique [0006] Adeno-associated virus (AAV) is a member of the parvoviridae family. The AAV genome comprises a linear single-stranded DNA molecule approximately 4.7 kilobases (kb) in length with two major open reading f...

Claims

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Application Information

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IPC IPC(8): A61K48/00C12N15/864
CPCC12N2750/14143A61K48/005C12N15/86C07K14/4702A61K48/0075A61K48/0083A61P21/00
Inventor J·M·哈特菲尔德R·E·霍奇D·费尔特纳J·巴莱迪耶M·梅里吉奥利B·K·卡斯帕A·A·卡斯帕
Owner NOVARTIS AG
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