Frataxin expression constructs
Inventors
SCHAUER, Stephen • Thomas, Darby • ROBINSON, Gregory • PYKETT, Mark • Thorn, Richard • GRUIS, Kirsten
Assignees
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Publication Number
US-11116852-B2
Publication Date
2021-09-14
Expiration Date
Abstract
The invention provides polynucleotides, vectors and viruses expressing frataxin and methods of treating Friedreich's Ataxia.
Core Innovation
The invention provides frataxin expression constructs for Friedreich’s ataxia. The constructs include nucleic acids encoding a human frataxin polypeptide having an amino acid sequence of SEQ ID NO:1, with the nucleic acid operably linked to defined 5′UTR and 3′UTR elements and a synthetic 3′ regulatory element. The 5′UTR is either RPL6-5′Splice or 5U2, and the 3′UTR is a synthetic 3′ regulatory element having the nucleic acid sequence of SEQ ID NO:7.
The constructs further include control elements that direct transcription and/or translation. In particular embodiments, the control element includes a UBC promoter (SEQ ID NO:3) combined with either an RPL6-5′Splice 5′UTR (SEQ ID NO:16) or a 5U2 5′UTR (SEQ ID NO:4), together with the synthetic 3′ regulatory element (SEQ ID NO:7). Related promoter embodiments referenced include CMV, EF1α, PGK1, a minimal frataxin promoter, and GAPDH 5′ regulatory element, as well as polyadenylation sequences such as SV40 early/late polyA or a human growth hormone polyadenylation sequence (hGH polyA; SEQ ID NO:5).
The invention also provides viral-vector embodiments and pharmaceutical compositions. Recombinant virions include vectors carrying the human frataxin nucleic acid operably linked to the specified 5′UTR/3′UTR configurations and transcription/translation control elements, with embodiments described as AAV vectors/virions including AAV5. Compositions are described as including the viral vector together with a pharmaceutically acceptable excipient, and the document includes discussion of mitochondrial targeting and optional inducible gene switch systems for expression control.
Claims Coverage
The partial content includes three independent claim sets covering: (i) a polynucleotide encoding functional human frataxin with specific 5′UTR and synthetic 3′ regulatory element combinations; (ii) a recombinant virion comprising a viral vector with the same regulatory-element-defined frataxin nucleic acid; and (iii) a composition comprising the viral vector and a pharmaceutically acceptable excipient. Across the independent claims, the main inventive elements are the defined human frataxin sequence (SEQ ID NO:1) and the operable linkage to either RPL6-5′Splice or 5U2 as the 5′UTR with a synthetic 3′ regulatory element having SEQ ID NO:7 as the 3′UTR under control of an element that directs transcription and/or translation.
Polynucleotide encoding functional human frataxin with defined UTRs
A polynucleotide comprising a nucleic acid molecule encoding a human frataxin polypeptide having an amino acid sequence of SEQ ID NO:1, wherein the nucleic acid molecule is operably linked to a 5′UTR and a 3′UTR, wherein the 5′UTR is RPL6-5′Splice and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; or the 5′UTR is 5U2 and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7, wherein the encoded human frataxin polypeptide is a functional frataxin protein.
Recombinant virion with frataxin encoding nucleic acid operably linked to defined UTRs and control element
A recombinant virion which comprises a viral vector, wherein said vector comprises a nucleic acid molecule encoding human frataxin operably linked to a 5′UTR, a 3′UTR, and a control element that directs transcription and/or translation, wherein the 5′UTR is RPL6-5′Splice and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; or the 5′UTR is 5U2 and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7.
Viral-vector composition with pharmaceutically acceptable excipient and defined UTRs
A composition comprising (a) a viral vector, wherein said vector comprises a nucleic acid molecule encoding human frataxin operably linked to a 5′UTR, a 3′UTR, and a control element that directs transcription and/or translation, wherein the 5′UTR is RPL6-5′Splice and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; or the 5′UTR is 5U2 and the 3′UTR is a synthetic 3′ regulatory element having a nucleic acid sequence of SEQ ID NO:7; and (b) a pharmaceutically acceptable excipient.
Across the independent claims, the scope centers on delivering or expressing a human frataxin polypeptide defined by SEQ ID NO:1, using a nucleic acid construct operably linked to either RPL6-5′Splice or 5U2 as the 5′UTR and a synthetic 3′ regulatory element having SEQ ID NO:7 as the 3′UTR, with transcription and/or translation directed by a control element. The claims further cover embodiments where the construct is provided as a recombinant virion (including viral-vector embodiments) and as a composition that additionally includes a pharmaceutically acceptable excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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