Anellovirus compositions and methods of use
Inventors
Weinstein, Erica Gabrielle • Kahvejian, Avak • Delagrave, Simon • Yozwiak, Nathan Lawrence • Lebo, Kevin James • Diaz, Fernando Martin • Nawandar, Dhananjay Maniklal • Tedstone, Ryan D. • Pitts, Jared David
Assignees
Ring Therapeutics Inc • Flagship Pioneering Innovations V Inc • Flagship Pioneering Inc
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Publication Number
US-11166996-B2
Publication Date
2021-11-09
Expiration Date
Abstract
This invention relates generally to viral vectors and viral particles based on Anelloviruses, which can be used to deliver an agent (e.g., an exogenous effector or an endogenous effector, e.g., a therapeutic effector) to a cell (e.g., a cell in a subject to be treated therapeutically). Described herein are anellosomes, anellovectors, and compositions and uses thereof.
Core Innovation
The invention provides a method of delivering a therapeutic polypeptide or nucleic acid to a subject using a pharmaceutical composition comprising an anellosome. The anellosome includes a proteinaceous exterior comprising an Anellovirus ORF1 polypeptide and a genetic element encapsulated by the proteinaceous exterior. The genetic element comprises a promoter operably linked to a heterologous sequence encoding the therapeutic polypeptide or nucleic acid and includes an Anellovirus 5′ UTR while excluding Anellovirus ORF1, ORF2, and ORF3 coding sequences or nonfunctional versions.
The disclosure further specifies that the Anellovirus ORF1 polypeptide may correspond to ORF1 from Alphatorquevirus, Betatorquevirus, or Gammatorquevirus, and provides ORF1-derived structural regions used to form the proteinaceous exterior, including an arginine-rich region, a jelly-roll domain, a hypervariable region, an N22 domain, and a C-terminal domain. Sequence embodiments are described with identity-based variant thresholds, including 70–100% identity for ORF1 sequences and at least 90% sequence identity to about 60 consecutive nucleotides of an Anellovirus 5′ UTR.
The delivery vehicle is presented as a pharmaceutical composition for administering anellosomes to a subject. Additional stated features include reduced immunogenicity, non-pathogenicity, detergent resistance, non-integrating behavior, and integration into the subject’s genome at a frequency less than 1%.
Claims Coverage
The consolidated claims coverage includes four inventive features across the provided items, centered on anellosome-based delivery and ORF1-defined sequence architecture. The claims focus on an Anellovirus ORF1 proteinaceous exterior, an encapsulated genetic element with a promoter linked to a heterologous therapeutic sequence, inclusion of an Anellovirus 5′ UTR, and exclusion of functional Anellovirus ORF1/ORF2/ORF3 coding sequences, with one claim adding a sequence-identity constraint to about 60 consecutive nucleotides of the Anellovirus 5′ UTR.
Anellosome with Anellovirus ORF1 proteinaceous exterior
A pharmaceutical composition comprising an anellosome that includes a proteinaceous exterior comprising an Anellovirus ORF1 polypeptide and a genetic element encapsulated by the proteinaceous exterior.
Promoter-linked heterologous therapeutic sequence
A genetic element comprising a promoter operably linked to a heterologous sequence encoding the therapeutic polypeptide or nucleic acid.
Anellovirus 5′ UTR in the genetic element
A genetic element comprising an Anellovirus 5′ UTR, including a nucleic acid sequence comprising at least 90% sequence identity to about 60 consecutive nucleotides of an Anellovirus 5′ UTR.
Exclusion of Anellovirus ORF1, ORF2, and ORF3 coding sequences
The genetic element does not comprise any sequence encoding Anellovirus ORF1, does not comprise any sequence encoding Anellovirus ORF2, and does not comprise any sequence encoding Anellovirus ORF3; alternatively, the claims allow nonfunctional Anellovirus ORF1/ORF2/ORF3.
The claims consistently define delivery using an anellosome whose exterior comprises Anellovirus ORF1 and whose genetic element carries a promoter-linked heterologous therapeutic sequence plus an Anellovirus 5′ UTR. They further require exclusion of functional Anellovirus ORF1/ORF2/ORF3 coding content, and one claim adds a specific 5′ UTR identity constraint.
Stated Advantages
Reduced immunogenicity characterized by efficacy retention versus an immune reference subject lacking immune response.
Reduced antibody specific immune response, reduced immune effector cell response, and reduced macrophage engulfment/uptake are described in the context of reduced immunogenicity.
Enhanced delivery performance including delivery into defined fractions of eukaryotic cells and delivery/copy-number performance thresholds are described in the disclosure.
Reduced immunogenicity versus conventional viral vectors.
Non-pathogenicity.
Detergent resistance.
Non-integrating behavior and low integration frequency.
Potency/purity quality control parameters to support effective and safe administration.
Documented Applications
Delivery of a therapeutic polypeptide or nucleic acid to a subject by administering a pharmaceutical composition comprising an anellosome.
Therapeutic polypeptide and nucleic acid delivery to subject cells, including regulatory nucleic acids such as miRNA and siRNA.
Immune reduction and delivery-performance assessment contexts include comparisons to an AAV immune reference and evaluation of antibody and cellular/macrophage immune responses.
Delivering a therapeutic nucleic acid including miRNA with a functional consequence of decreasing gene expression in the subject.
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