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 • US Department of Health and Human Services
Publication Number
US-11802283-B2
Publication Date
2023-10-31
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 compounds modulate aberrant splicing of LMNA pre-mRNA by hybridizing to target regions within LMNA pre-mRNA, particularly exon 11, to prevent the production of the mutant progerin protein associated with Hutchinson-Gilford progeria syndrome (HGPS). The antisense oligonucleotides of the invention range from 10 to 40 nucleobases and may be conjugated to cell penetrating peptides (CPPs) to facilitate effective cellular delivery.
HGPS is a rare genetic disorder caused primarily by a de novo silent substitution mutation in exon 11 of the LMNA gene. This mutation activates a cryptic splice donor site, leading to a truncated lamin A protein, progerin, which accumulates on the nuclear membrane and results in premature aging symptoms and early death. Existing therapies lack specific means to inhibit progerin production effectively. The problem addressed by the invention is the need for oligonucleotides that specifically modulate splicing of LMNA pre-mRNA to eliminate progerin expression and thereby treat HGPS and related progeroid laminopathies.
The invention discloses modified antisense oligonucleotides comprising specific targeting sequences complementary to the cryptic splice site within LMNA exon 11 mRNA, including sequences of SEQ ID NOS: 3 and 4, and conjugated to differing CPPs with various linker moieties for enhanced cellular uptake. Pharmaceutical compositions containing these antisense compounds and methods for their therapeutic administration in treating HGPS, progeroid laminopathies, age-related conditions, and cardiovascular diseases associated with aberrant LMNA splicing are also provided.
Claims Coverage
The patent includes four claims focusing on methods for treating Hutchinson-Gilford Progeria Syndrome (HGPS) using specific antisense oligonucleotide compounds and pharmaceutical compositions.
Method of treating HGPS with specific antisense oligomer compounds
Administering to a subject an antisense oligomer compound, or pharmaceutically acceptable salt thereof, specifically selected antisense oligomers targeting LMNA pre-mRNA for splice modulation to reduce progerin expression.
Selection of antisense oligomer compounds for therapy
Using antisense oligomer compounds which correspond to sequences and structural formulas detailed in the disclosure to effectively target the cryptic splice site in LMNA pre-mRNA.
Treatment method employing pharmaceutical compositions comprising antisense compounds
Administering pharmaceutical compositions containing antisense oligomer compounds of formula (Vb) to treat HGPS by modulating aberrant LMNA pre-mRNA splicing.
Use of antisense oligomer compounds of formula (VIb) in pharmaceutical compositions for HGPS treatment
Employing antisense oligomer compounds of formula (VIb) within pharmaceutical compositions as therapeutic agents to treat HGPS via inhibition of progerin synthesis.
The claims collectively cover therapeutic methods involving the administration of specific antisense oligomers and their pharmaceutical compositions designed to modulate LMNA pre-mRNA splicing and reduce progerin expression in subjects with HGPS.
Stated Advantages
The antisense oligonucleotides effectively reduce expression of mutant LMNA mRNA isoforms encoding progerin, addressing the underlying cause of HGPS.
Conjugation to cell-penetrating peptides enhances cellular uptake and delivery of antisense compounds, improving therapeutic potential.
Pharmaceutical compositions enable versatile delivery routes and dosing regimens suitable for treating progeroid laminopathies and related conditions.
Documented Applications
Treatment of Hutchinson-Gilford progeria syndrome (HGPS) by administering antisense oligonucleotides targeting LMNA pre-mRNA to reduce progerin expression.
Methods to treat progeroid laminopathies and related progeroid diseases by modulating LMNA splicing using antisense oligonucleotides.
Therapeutic use in age-related conditions and cardiovascular diseases such as atherosclerosis associated with aberrant LMNA splicing.
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