IP Library › Granted Patent US 12,649,006
Granted Patent B2
US 12,649,006 · App. 17/796,064 · Granted Jun 9, 2026

Gene therapy for treating CDKL5 deficiency disorder

Inventors: Sharyl Lynne Fyffe-Maricich (Novato, CA); Matthew Scott Fuller (Millis, MA); Margaret Caroline Wright (San Rafael, CA); Lorelei Ioana Stoica (Acton, MA); Stewart Craig (Cambridge, MA); Sean Christopher Daugherty (Petaluma, CA)
Assignee: Ultragenyx Pharmaceutical Inc.
A61K48/0058A61K31/573A61K35/761A61K48/0075A61P25/28
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Quick Facts
Patent No.
US 12,649,006
App. No.
17/796,064
Granted
Jun 9, 2026
Kind
B2
Abstract

This present disclosure provides adeno-associated viral vectors, recombinant adeno-associated vims (rAAV), and methods of their use in gene therapy for treating CDKL5 deficiency disorder (CDD). Also provided are pharmaceutical compositions comprising an rAAV of the invention and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions may be useful in gene therapy for the treatment of CDD caused by mutations in CDKL.

Claims (35)

1 . A recombinant adeno-associated virus (rAAV), wherein said rAAV comprises an AAV capsid and a vector genome packaged therein, wherein said vector genome comprises:

(a) a promoter sequence; and

(b) a coding sequence for CDKL5, wherein said coding sequence comprises a sequence which is at least 95% identical to a sequence selected from SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, and 8.

2 . The rAAV according to claim 1 , wherein the AAV capsid is from an AAV of serotype 8, 9, 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, rh10, AAV9 variant, or hu37.

3 . The rAAV according to claim 1 , wherein the promoter sequence is any one of:

(i) a neuron-specific promoter sequence selected from any one of a human synapsin 1 (SYN1) promoter sequence, a mouse calcium/calmodulin-dependent protein kinase II (CaMKII) promoter sequence, a rat tubulin alpha I (Ta1) promoter sequence, a rat neuron-specific enolase (NSE) promoter sequence, a human neuron-specific enolase (ENO2) promoter sequence, a human platelet-derived growth factor-beta chain (PDGF) promoter sequence, a human BM88 promoter sequence, and a neuronal nicotinic receptor β2 (CHRNB2) promoter sequence; and

(ii) a chicken β-actin (CBA) promoter sequence, a cytomegalovirus (CMV) immediate early gene promoter sequence, a transthyretin (TTR) promoter sequence, a thyroxine binding globulin (TBG) promoter sequence, an alpha-1 anti-trypsin (A1AT) promoter sequence, and a CDKL5 gene-specific endogenous promoter sequence.

4 . The rAAV according to claim 3 , wherein the neuron-specific promoter sequence is selected from any one of:

(a) a human synapsin 1 (SYN1) promoter sequence comprising the sequence of SEQ ID NO: 12,

(b) a human SYN1 promoter sequence consisting of SEQ ID NO: 12,

(c) a CBA promoter sequence comprising the sequence of SEQ ID NO: 13,

(d) a CBA promoter sequence consisting of SEQ ID NO: 13, and

(e) a CDKL5 gene-specific endogenous promoter that comprises a nucleotide sequence of at least 15 continuous nucleotides which is at least 95% identical to an equal length region of the sequence of SEQ ID NO: 14.

5 . The rAAV according to claim 1 , wherein the vector genome further comprises a 5′-ITR sequence, a 3′-ITR sequence, or both.

6 . The rAAV according to claim 5 , wherein:

(a) the 5′-ITR sequence and/or the 3′-ITR sequence are from an AAV2 source; or

(b) the 5′-ITR sequence and/or the 3′-ITR sequence are from a non-AAV2 source.

7 . The rAAV according to claim 1 , wherein the vector genome further comprises a polyadenylation signal sequence selected from an SV40 polyadenylation signal sequence, a bovine growth hormone (BGH) polyadenylation signal sequence, and a rabbit beta globin polyadenylation signal sequence.

8 . The rAAV according to claim 7 , wherein the SV40 polyadenylation signal sequence comprises or consists of the nucleic acid sequence of SEQ ID NO: 15.

9 . The rAAV according to claim 1 , wherein the vector genome further comprises one or more enhancer sequences selected from a cytomegalovirus (CMV) immediate early gene enhancer sequence, a transthyretin enhancer (enTTR) sequence, a chicken β-actin (CBA) enhancer sequence, an En34 enhancer sequence, and an apolipoprotein E (ApoE) enhancer sequence.

10 . The rAAV according to claim 9 , wherein the enhancer sequence is located upstream of the promoter sequence.

11 . The rAAV according to claim 1 , wherein the vector genome further comprises one or more intron sequences selected from an SV40 Small T intron sequence, a rabbit hemoglobin subunit beta (rHBB) intron sequence, a human beta globin IVS2 intron sequence, a β-globin/IgG chimeric intron sequence, and an hFIX intron sequence.

12 . A composition comprising the rAAV of claim 1 and a pharmaceutically acceptable carrier.

13 . A polynucleotide which comprises a nucleic acid sequence that is:

(a) at least 95% identical to the sequence of SEQ ID NO: 19;

(b) 100% identical to the sequence of SEQ ID NO: 19;

(c) at least 95% identical to the sequence of SEQ ID NO: 20; or

(d) 100% identical to the sequence of SEQ ID NO: 20.

14 . The rAAV according to claim 5 , wherein the 5′-ITR sequence and/or the 3′-ITR sequence are from an AAV2 source and comprise the nucleic acid sequence of SEQ ID NO: 11.

15 . A recombinant adeno-associated virus (rAAV), wherein said rAAV comprises an AAV capsid and a vector genome packaged therein, wherein said vector genome comprises:

(a) an AAV 5′-inverted terminal repeat (ITR) sequence of SEQ ID NO: 11;

(b) a human synapsin 1 (SYN1) promoter sequence of SEQ ID NO: 12;

(c) a nucleic acid sequence of SEQ ID NO: 1 encoding CDKL5;

(d) an SV40 polyadenylation signal sequence of SEQ ID NO: 15; and

(e) an AAV 3′-ITR sequence of SEQ ID NO: 11.

Continuity (3)
Provisional Application 63090492 · Oct 12, 2020
Provisional Application 62976483 · Feb 14, 2020
Related Publication 20230054144A1 · Feb 23, 2023
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