Adeno-associated virus vectors for treatment of Rett syndrome
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Publication Number
US-12104163-B2
Publication Date
2024-10-01
Expiration Date
Abstract
The disclosure provides nucleic acids (comprising AAV expression cassettes), AAV vectors, and compositions for use in methods for treating and/or delaying the onset of diseases associated with mutations in the mecp2 gene, such as Rett Syndrome. Also, provided herein are methods for treating and/or delaying the onset of brain-derived neurotrophic factor (BDNF)-associated diseases.
Core Innovation
The invention provides a nucleic acid comprising an adeno-associated virus (AAV) expression cassette arranged from 5′ to 3′ with a 5′ inverted terminal repeat (ITR), a minimal human Arc gene promoter (hArcMin) set forth by SEQ ID no. 12, a Rett Syndrome-associated gene, and a 3′ ITR. The cassette configuration is intended to enable expression driven by the minimal Arc gene promoter within an AAV expression cassette framework for Rett Syndrome-associated genes.
In the described constructs, the promoter element is associated with a synaptic activity response element and neuronal activity-dependent transcription factors, including CREB, MEF2, SRF, and Elk-1, as reflected in reporter activity using an hSARE-hArcMin promoter system. The approach emphasizes activity dependence by using the synaptic activity response element with the minimal Arc promoter to drive gene expression in response to neuronal activity modulation.
The constructs also include defined 3′ regulatory components, including options for BDNF-associated elements such as BDNF short 3′ UTR (SEQ ID NO: 8) or BDNF long 3′ UTR (SEQ ID NO: 10), and a polyadenylation signal (e.g., bGH polyA; SEQ ID NO: 9) located between the Rett Syndrome-associated gene and the 3′ ITR. The described system is further tied to AAV vector expression cassette design and can incorporate specified AAV genome-derived ITR sources and AAV capsid/serotype options for therapeutic CNS neuronal delivery.
The described therapeutic context focuses on AAV gene therapy constructs for Rett syndrome and MECP2-related conditions, including using Rett Syndrome-associated genes such as BDNF. The document further reports in vivo testing in mecp2 mutant mice to assess BDNF expression effects on symptom severity and delay, alongside activity-dependent promoter function characterization using reporter fluorescence readouts.
Claims Coverage
The independent claim is clm-00001. It defines the core claim coverage as a nucleic acid containing an AAV expression cassette with a 5′ ITR, a minimal human Arc gene promoter (hArcMin) set forth by SEQ ID no. 12, a Rett Syndrome-associated gene, and a 3′ ITR.
AAV expression cassette with hArcMin and Rett Syndrome-associated gene
A nucleic acid comprising an adeno-associated virus (AAV) expression cassette from 5′ to 3′ including a 5′ inverted terminal repeat (ITR), a minimal human Arc gene promoter (hArcMin) set forth by SEQ ID no. 12, a Rett Syndrome-associated gene, and a 3′ ITR.
The claim coverage centers on an AAV expression cassette in which the minimal human Arc gene promoter (hArcMin) defined by SEQ ID no. 12 drives expression of a Rett Syndrome-associated gene within an arrangement flanked by 5′ and 3′ ITRs.
Stated Advantages
Not explicitly described in patent.
Documented Applications
AAV gene therapy constructs for Rett syndrome and MECP2-related conditions, including therapeutic administration with CNS neuronal delivery and expression testing in mecp2 mutant mice with assessment of BDNF expression effects on symptom severity and delay.
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