Compositions and methods for treating phenylketonuria
Inventors
Lahusen, Tyler • Pauza, Charles David
Assignees
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Publication Number
US-11820999-B2
Publication Date
2023-11-21
Expiration Date
Abstract
A lentiviral vector system for expressing a lentiviral particle is disclosed. The lentiviral vector system includes a therapeutic vector. The therapeutic vector comprises a phenylalanine hydroxylase (PAH) sequence for expressing at least one of PAH or a variant thereof, wherein the PAH sequence is truncated.
Core Innovation
The invention provides a viral vector comprising a phenylalanine hydroxylase (PAH) sequence for expressing at least one of PAH or a variant thereof. The PAH sequence is truncated, with the truncated sequence defined as SEQ ID NO: 3, SEQ ID NO: 4, or a sequence having 80%, 85%, 90%, 95%, or 100% identity to SEQ ID NO: 3 or SEQ ID NO: 4.
The system also includes at least one small RNA sequence that binds a predetermined complementary mRNA sequence and is directed to endogenous PAH mRNA using a predetermined complementary targeting concept. The document describes truncated versus full-length PAH 3′ UTR forms and their different responses to particular shRNA constructs, including dependence effects reported with shRNA selection.
The vector architecture further includes regulatory/promoter components and viral packaging/replication/structural elements. These include liver-specific promoter options, including hAAT, an H1 promoter for small RNA control, WPRE, ΔU3 3′ LTR, and additional viral components and backbone or polyA/ITR regions consistent with a viral vector architecture that accommodates the truncated PAH expression cassette.
Claims Coverage
The claim set centers on a viral vector with a truncated phenylalanine hydroxylase (PAH) sequence for expressing PAH or a PAH variant, with truncation tied to SEQ ID NO: 3 or SEQ ID NO: 4 or specified identity levels to those sequences. It further includes small RNA elements, promoter assignment, and sequence-identity constraints for those small RNA elements.
Truncated phenylalanine hydroxylase sequence for viral expression
A viral vector comprising a phenylalanine hydroxylase (PAH) sequence for expressing at least one of PAH or a variant thereof, wherein the PAH sequence is truncated, and wherein the truncated sequence is SEQ ID NO: 3, SEQ ID NO: 4, or a sequence that has 80%, 85%, 90%, 95%, or 100% identity to SEQ ID NO: 3 or SEQ ID NO: 4.
Small RNA sequence targeting a predetermined complementary mRNA sequence
The viral vector further comprises at least one small RNA sequence that binds a predetermined complementary mRNA sequence.
Distinct promoters for small RNA and PAH
The at least one small RNA sequence is driven by a first promoter and the PAH sequence is driven by a second promoter.
H1 promoter and liver-specific promoter assignment
The first promoter is an H1 promoter and the second promoter is a liver-specific promoter.
Liver-specific promoter comprising an hAAT promoter
The liver-specific promoter comprises a hAAT promoter.
Percent-identity constraints for small RNA sequences relative to SEQ ID NO: 5 or SEQ ID NO: 6
The at least one small RNA sequence comprises a sequence with at least one of the specified sequence-identity percentages relative to SEQ ID NO: 5 or SEQ ID NO: 6.
The claims focus on expression of PAH or a PAH variant from a viral vector using a truncated PAH sequence defined by SEQ ID NO: 3/SEQ ID NO: 4 or identity-defined equivalents, with optional small RNA targeting, promoter separation, and identity thresholds for the small RNA sequences.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Phenylketonuria (PKU) treatment.
In vivo context using a Pah(enu2) mouse model after direct liver injection to demonstrate phenylalanine-related outcomes and growth correction.
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