Modified antisense oligomers for exon inclusion in spinal muscular atrophy
Inventors
Passini, Marco A. • Hanson, Gunnar J.
Assignees
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Publication Number
US-12121532-B2
Publication Date
2024-10-22
Expiration Date
Abstract
The present disclosure relates to modified antisense oligomers and related compositions and methods for increasing the expression of functional SMN protein and methods for treating spinal muscular atrophy and relates to inducing inclusion of exon 7 in SMN2 mRNA.
Core Innovation
The invention relates to modified antisense oligomer compounds defined by formula (VII), or pharmaceutically acceptable salts thereof. Each Nu is a nucleobase, and the nucleobases taken together form a targeting sequence. The targeting sequence comprises, is selected from, or is a fragment of at least 8 contiguous nucleotides of sequences selected from SEQ ID NOS: 35-37, and Z is an integer from 6 to 38.
A moiety T is defined by a specified structural formula and includes substituent groups R1 and R2, with each R1 independently selected from the defined options and R2 selected from H, acyl, trityl, 4-methoxytrityl, and C1-C6 alkyl. The disclosure further states that at least one R1 satisfies the additional selection condition, and provides examples of modified antisense oligomer embodiments and phosphoramidate or phosphonate-linked structures.
The document also describes embodiments involving a cell-penetrating peptide (CPP) attached to a linker moiety via an amide bond, with example CPP sequences represented by SEQ ID NOS: 17-32. The modified antisense oligomer compounds are presented with structural embodiments and sequence-defined variants, including PMO-based and related oligomer forms.
Claims Coverage
The independent claims include a compound of formula (VII), a pharmaceutical composition comprising that compound, and a method of treating spinal muscular atrophy (SMA) by administering that compound. Across these independent claims, the core inventive features are the formula (VII) compound definition, the targeting sequence limited to SEQ ID NOS: 35-37 or fragments of at least 8 contiguous nucleotides, the integer Z range of 6 to 38, and the moiety T defined by R1 and R2 selection rules with at least one R1 meeting an additional condition.
Formula (VII) compound with nucleobase targeting sequence
A compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each Nu is a nucleobase which taken together form a targeting sequence and Z is an integer from 6 to 38.
Targeting sequence restricted to SEQ ID NOS: 35-37 and fragments
The targeting sequence comprises a sequence selected from SEQ ID NOS: 35-37, is selected from SEQ ID NOS: 35-37, or is a fragment of at least 8 contiguous nucleotides of a targeting sequence selected from SEQ ID NOS: 35-37.
Moiety T with defined R1 and R2 substituent options
T is a moiety of the formula, wherein each R1 is independently selected from the defined options, R2 is selected from H, acyl, trityl, 4-methoxytrityl, and C1-C6 alkyl, and at least one R1 satisfies the additional selection condition.
Pharmaceutical composition comprising formula (VII) compound
A pharmaceutical composition comprising a compound of formula (VII) or a pharmaceutically acceptable salt thereof with the same Nu, Z, targeting sequence, and T limitations.
Method of treating spinal muscular atrophy using formula (VII) compound
A method of treating spinal muscular atrophy (SMA) in a subject in need thereof comprising administering an effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt thereof with the same Nu, Z, targeting sequence, and T limitations.
Across the independent claims, coverage centers on formula (VII) compounds and salts defined by a nucleobase targeting sequence limited to SEQ ID NOS: 35-37 or fragments of at least 8 contiguous nucleotides, a Z integer range from 6 to 38, and a moiety T with specified R1 and R2 selections including an additional condition on at least one R1. The same structural framework is carried into a pharmaceutical composition claim and a method claim for treating spinal muscular atrophy (SMA).
Stated Advantages
Increase exon 7-containing SMN2 mRNA and increase functional SMN protein.
Induce SMN2 exon 7 inclusion.
In vivo functional outcomes are reported in an SMN7 mouse, including survival, weight, reflex/strength, and western blots.
Documented Applications
Treating spinal muscular atrophy (SMA) in a subject in need thereof by administering an effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt thereof.
In vitro exon-7 inclusion analysis and in vivo SMN7 mouse functional outcomes are documented.
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