Frataxin expression constructs having engineered promoters and methods of use thereof

Inventors

Patzke, Holger • Hou, Jinzhao • Wang, Hongxing • Shu, Yanqun • Goulet, Martin • Sah, Dinah Wen-Yee

Assignees

Voyager Therapeutics Inc

Abstract

The disclosure relates to compositions and methods for altering, e.g., enhancing, the expression of frataxin (FXN), whether in vitro and/or in vivo including, but not limited to, the exploitation of engineered promoters. Such compositions include delivery via administration of an adeno-associated viral (AAV) particle. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, or suspected of having Friedreich's ataxia or another neuromuscular or neurological condition resulting from a deficiency in the quantity and/or function of frataxin or associated with decreased expression or protein levels of frataxin.

Core Innovation

The invention relates to adeno-associated viral (AAV) vector genomes and engineered promoter systems for delivery of a frataxin protein (FXN). The disclosure includes an engineered promoter and a nucleic acid sequence encoding frataxin, with sequence identity constraints defined relative to specified SEQ ID sequences, including an engineered promoter having at least 90% sequence identity to SEQ ID NO: 1742 over the full length of the engineered promoter.

The disclosed genome architecture includes AAV expression vector elements such as inverted terminal repeats (ITRs), including AAV2 ITRs, intron elements, microRNA binding sites, polyadenylation sequences, optional filler sequences, tag sequences, junction sequences, and HA tag features. It also describes AAV vector genome formats including ssAAV and scAAV, sequence-defined payloads related to SEQ ID NO: 1797, and corresponding AAV particles and cells.

The document ties the AAV capsid and genome engineering to Friedreichs ataxia and other decreased-frataxin disorders, and it states that delivery of FXN is contemplated. It also describes in vivo promoter selection with persistent frataxin expression and biodistribution across brain/DRG tissues, together with functional testing in a Friedreichs ataxia model.

Claims Coverage

The independent claims cover three main categories of AAV vector genomes distinguished by engineered promoter sequence identity, by a defined genome sequence (SEQ ID NO: 1797), and by downstream therapeutic forms that include AAV particles, cells, pharmaceutical compositions, and treatment methods. Across the independent claims, the inventive coverage centers on sequence identity thresholds and on the therapeutic use of the resulting AAV particles for disorders associated with decreased frataxin protein levels.

Overall, claim coverage is anchored by sequence-identity requirements for either an engineered promoter used with a frataxin-encoding nucleic acid or a defined AAV vector genome sequence (SEQ ID NO: 1797). Dependent claim coverage further includes constructs in AAV particle form, cells containing the vector genome, pharmaceutical compositions with a pharmaceutically acceptable excipient, and treatment of Friedreichs ataxia or another disorder associated with decreased frataxin protein levels by administering an effective amount of the relevant AAV particle.

Stated Advantages

Documented Applications