Oligonucleotide analogues targeting human LMNA
Inventors
Erdos, Michael R. • Collins, Francis S. • Cao, Kan • Kole, Ryszard • Bestwick, Richard Keith • Gordon, Leslie B.
Assignees
Progeria Research Foundation • University of Maryland Baltimore • Progeria Research Foundation Inc • Sarepta Therapeutics Inc • University of Maryland College Park • US Department of Health and Human Services
Publication Number
US-10822608-B2
Publication Date
2020-11-03
Expiration Date
2037-04-28
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Abstract
Provided are LMNA-targeted antisense oligonucleotides for reducing expression of one or more aberrantly spliced LMNA mRNA isoforms that encode progerin.
Core Innovation
The invention provides LMNA-targeted antisense oligonucleotides designed to reduce expression of aberrantly spliced LMNA mRNA isoforms that encode progerin. These antisense oligomers are modified and comprise targeting sequences complementary to regions within LMNA pre-mRNA to modulate aberrant splicing. The antisense compounds may include peptide conjugates such as cell penetrating peptides (CPPs) to facilitate intracellular delivery, with specified sequences and linker moieties. The oligonucleotides span lengths of about 8 to 40 nucleobases with targeting sequences specifically complementary to sequences in exon 11 of the human LMNA gene.
The problem addressed by the invention arises from Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature arteriosclerosis and accelerated aging caused by a point mutation in the lamin A (LMNA) gene. This mutation activates a cryptic splice donor site resulting in production of progerin, a dominant negative mutant lamin A protein causing nuclear abnormalities. Existing therapies are limited, and there is a need for oligonucleotides that modulate splicing of LMNA pre-mRNA to eliminate progerin expression. The invention seeks to provide antisense oligonucleotides and methods effective in correcting aberrant splicing linked to HGPS and related laminopathies.
Claims Coverage
The patent contains four claims with two independent claims covering both the antisense oligomer compounds and pharmaceutical compositions. The claims focus on specific antisense oligomer structures and their pharmaceutical formulations.
Antisense oligomer compounds targeting LMNA pre-mRNA
Compounds comprising antisense oligomers or pharmaceutically acceptable salts thereof, specifically selected from defined oligonucleotide sequences (e.g., formula (Vb)) targeting exon 11 of LMNA pre-mRNA to inhibit aberrant splicing that produces progerin.
Pharmaceutical compositions comprising antisense oligomers
Pharmaceutical compositions containing an antisense oligomer compound of defined formula (e.g., formula (Vb) or formula (VIb)) formulated with pharmaceutically acceptable carriers for therapeutic use against LMNA-related diseases.
The claims cover antisense oligomers targeting aberrant LMNA mRNA splicing sequences and their pharmaceutical compositions, emphasizing specific oligonucleotide sequences and conjugation methods that improve delivery and efficacy in treating diseases associated with progerin expression such as HGPS.
Stated Advantages
The antisense oligonucleotides effectively reduce aberrant LMNA splicing and progerin expression, addressing the underlying cause of HGPS.
Phosphorodiamidate morpholino oligonucleotides (PMOs) and splice-switching oligonucleotides (SSOs) used are resistant to nucleases, increasing stability and effectiveness in vivo and in vitro.
Conjugation to cell penetrating peptides enhances cellular uptake and delivery of antisense oligonucleotides.
Documented Applications
Treatment of progeroid laminopathies such as Hutchinson-Gilford progeria syndrome (HGPS).
Methods of treating age-related conditions and cardiovascular diseases, including atherosclerosis, connected to aberrant LMNA expression.
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