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A composition comprising an expression cassette having a nucleic acid sequence encoding one or more elements of a gene editing system that targets UBE3A-ATS on a paternal allele in a neuron of a patient having Angelman syndrome is provided. Also provided is a method for treating one or more symptoms of Angelman syndrome (AS) in a patient having deficient UBE3A expression in neurons, wherein the method comprises delivering a nucleic acid sequence that encodes one or more elements of a gene editing system that targets UBE3A-ATS to modify the UBE3A-ATS coding sequence and provide for expression of paternal UBE3A.

Titel:	COMPOSITIONS AND USES THEREOF FOR TREATMENT OF ANGELMAN SYNDROME
Link:	Diesen Eintrag von USPTO anschauen (Volltext)
Veröffentlichung:	2023
Medientyp:	Patent
Sonstiges:	Nachgewiesen in: USPTO Patent Applications Sprachen: English Document Number: 20230167438 Publication Date: June 1, 2023 Appl. No: 17/997004 Application Filed: April 27, 2021 Claim: 1. An expression cassette comprising a nucleic acid sequence encoding one or more elements of a gene editing system that targets and introduces a mutation in UBE3A-ATS on a paternal allele in a neuron of a patient having Angelman syndrome and regulatory elements that direct expression thereof in a target cell, thereby unsilencing the paternal UBE3A allele and permitting expression of the UBE3A gene product. Claim: 2. The expression cassette according to claim 1, wherein the gene editing system is CRISPR/Cas, a meganuclease, a zinc-finger nuclease, or a TALEN. Claim: 3. The expression cassette according to claim 1, wherein the nucleic acid encodes a gene editing nuclease and/or a targeting sequence specific for UBE3A-ATS. Claim: 4. The expression cassette according to claim 1, wherein the gene-editing system comprises a CRISPR-associated nuclease and an sgRNA having a sequence that specifically binds a UBE3A-ATS target sequence. Claim: 5. The expression cassette according to claim 4, wherein the CRISPR endonuclease is Cas9, optionally SaCas9. Claim: 6. The expression cassette according to claim 1, wherein the expression cassette comprises a sequence encoding any of SEQ ID NOs: 1-32. Claim: 7. The expression cassette according to claim 1, wherein (a) the UBE3A-ATS target sequence is downstream of the UBE3A 3′UTR; and/or (b) the target sequence is located at chr15: 25,278,409-25,333,728 (hg38 genome assembly) and/or in a sequence of UBE3A-ATS complementary to the region between the UBE3A 3′UTR and SNORD109B ORF on chromosome 15. Claim: 8. (canceled) Claim: 9. The expression cassette according to claim 1, wherein the target cell is a cell of the CNS. Claim: 10. The expression cassette according to claim 1, wherein the regulatory elements comprise (a) a neuron-specific promoter, optionally wherein the promoter is a synapsin promoter; and/or (b) an enhancer. Claim: 11.-12. (canceled) Claim: 13. A plasmid comprising the expression cassette according to claim 1. Claim: 14. (canceled) Claim: 15. A recombinant adeno-associated virus (rAAV) useful as a CNS-directed therapeutic for treatment of Angelman syndrome (AS), the rAAV comprising an AAV capsid, and a vector genome packaged therein, said vector genome comprising: (a) an AAV 5′ inverted terminal repeat (ITR); (b) a nucleic acid sequence encoding one or more elements of a gene editing system that targets UBE3A-ATS; (c) regulatory elements that direct expression of the one or more elements of the gene editing system; and (d) an AAV 3′ ITR. Claim: 16. The rAAV according to claim 15, wherein the gene targeting system comprises a CRISPR endonuclease and a sgRNA that specifically binds a UBE3A-ATS target sequence. Claim: 17. The rAAV according to claim 15 or 16, wherein the CRISPR endonuclease is Cas9. Claim: 18. The rAAV according to claim 15, wherein the regulatory elements comprise (a) a neuron-specific promoter, optionally wherein the promoter is a synapsin promoter; and/or (b) an enhancer. Claim: 19. (canceled) Claim: 20. The rAAV according to claim 15, wherein the capsid is an AAV9 capsid, or variant thereof, or an AAVhu68 capsid, or variant thereof. Claim: 21. The rAAV according to claim 15, wherein the AAV capsid is an AAVhu68 capsid generated from expression of the nucleic acid sequence of SEQ ID NO: 54. Claim: 22. A pharmaceutical composition comprising at least the rAAV according to claim 15 and a physiologically compatible carrier, buffer, adjuvant, and/or diluent. Claim: 23. (canceled) Claim: 24. A method for treating one or more symptoms of Angelman syndrome (AS) in a patient having deficient UBE3A expression in neurons, said method comprising delivering a nucleic acid sequence that encodes one or more elements of a gene editing system that targets a sequence in UBE3A-ATS downstream of the UBE3A 3′UTR to modify the UBE3A-ATS coding sequence, thereby unsilencing UBE3A expression on a paternal allele of a patient having a deficiency in UBE3A expression from a maternal allele and providing for expression of the UBE3A gene product from the paternal allele. Claim: 25. The method according to claim 24, wherein (a) the modification is an indel, deletion, insertion, inversion, or other disruption in the UBE3A-ATS coding sequence; (b) the modification is introduced in the human UBE3A-ATS in the region spanning the UBE3A 3′UTR and SNORD109B; and/or (c) the target sequence is located at chr15: 25,278,409-25,333,728 (hg38 genome assembly) and/or in a sequence of UBE3A-ATS complementary to the region between the UBE3A 3′UTR and SNORD109B ORF on chromosome 15. Claim: 26.-27. (canceled) Claim: 28. The method according to claim 24, wherein the symptoms are selected from one or more of: delayed development, intellectual disability, severe speech impairment, ataxia and/or epilepsy. Claim: 29. (canceled) Current International Class: 12; 12; 12; 12; 61

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COMPOSITIONS AND USES THEREOF FOR TREATMENT OF ANGELMAN SYNDROME