Gene therapies for lysosomal disorders
Inventors
Abeliovich, Asa • Heckman, Laura • RHINN, Herve
Assignees
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Publication Number
US-10689625-B2
Publication Date
2020-06-23
Expiration Date
Abstract
The disclosure relates, in some aspects, to compositions and methods for treatment of diseases associated with aberrant lysosomal function, for example Parkinson's disease (PD) and Gaucher disease. In some embodiments, the disclosure provides expression constructs comprising a transgene encoding beta-Glucocerebrosidase (GBA) or a portion thereof alone or in combination with one or more PD-associated genes. In some embodiments, the disclosure provides methods of Parkinson's disease by administering such expression constructs to a subject in need thereof.
Core Innovation
The invention relates to rAAV-based lysosomal gene therapy for Parkinson’s disease and Gaucher disease by providing rAAV expression constructs that encode lysosomal and PD-associated gene products. The constructs express one or more proteins selected from lysosomal acid β-glucocerebrosidase (GBA1/β-glucocerebrosidase), prosaposin (PSAP), lysosomal membrane protein 2 (LIMP2/SCARB2), GBA2, GALC, CTSB, SMPD1, GCH1, RAB7L1, VPS35, IL-34, TREM2, TMEM106B, and PGRN/progranulin, either singly or in combinations.
The constructs include AAV inverted terminal repeats (ITRs) flanking the expression cassette and multiple promoter options, including CBA, CAG, CD68, and JeT, with promoter configurations described as Pol II/Pol III promoters. Post-transcriptional elements are included, including WPRE, and polyA tails are described, including bGH polyA signal. Multigene expression architectures are described using IRES, 2A/T2A self-cleaving peptides, or polycistronic architectures.
A further feature is modification of the rAAV ITR 20D/21 region positioning through modified 20D/21/20S sequences for outside versus inside positions in the vector design. The document indicates that such modified configurations are aimed at improving encapsidation and transduction and reducing toxicity relative to alternative configurations. The partial content also describes rAAV capsid choices, including AAV9 and AAVrh.10, and CNS delivery contexts including intracerebroventricular injection and convection enhanced delivery.
The partial content further states that the therapy is supported by in vitro and in vivo examples including assessments of expression-related outcomes such as GCase activity and reductions of substrates, together with vector biodistribution measurements. It also describes in vitro validation of knockdown for α-Synuclein (SNCA) and TMEM106B in HEK293 cells and rAAV transduction comparisons related to D-region placement, as well as progranulin vector testing in PGRN-deficient mice.
Claims Coverage
Not explicitly described in patent.
Not explicitly described in patent.
Stated Advantages
Improved encapsidation/transduction for modified ITR 20D/21/20S configurations.
Reduced toxicity for modified configurations relative to alternative designs.
Documented Applications
Treatment or therapeutic application for Parkinson’s disease using lysosomal gene therapy with rAAV expression constructs.
Treatment or therapeutic application for Gaucher disease using lysosomal gene therapy with rAAV expression constructs.
Optional Parkinson’s disease-relevant inhibitory targeting of α-Synuclein (SNCA/SCNA) and/or TMEM106B via inhibitory nucleic acids within the lysosomal rAAV framework.
CNS administration contexts described include intracerebroventricular injection and convection enhanced delivery, including delivery related to cisterna magna.
Evaluation in a CBE mouse model with outcome measures including GCase activity and substrate reductions, behavioral tests, and vector biodistribution.
Evaluation in PGRN-deficient mice with progranulin vector testing.
In vitro validation using HEK293 cells for inhibitory nucleic acid knockdown targeting SNCA and TMEM106B and for transduction comparisons related to D-region placement.
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