Anc80 encoding sphingolipid-metabolizing proteins

Inventors

ELIYAHU, Efrat • VINCEK, Adam • Katz, Michael

Assignees

Icahn School of Medicine at Mount Sinai

Abstract

The present disclosure pertains to the use of an Anc80 viral vector that encodes a sphingolipid-metabolizing protein such as acid ceramidase to achieve expression of the sphingolipid-metabolizing protein in a mammalian cell or group of cells. Expression of the protein from the Anc80 vector reduces high levels of ceramide in the cell that lead to cell death or senescence.

Core Innovation

The invention relates to restoring heart function in a subject following ischemia, reperfusion injury or myocardial infarction (MI) by directly administering an Anc80 viral vector that comprises a nucleotide sequence encoding an acid ceramidase protein operatively linked to an expression control sequence in vivo to cardiac cells. The approach is described in the context of sphingolipid metabolism, where ceramide is converted to sphingosine and then to sphingosine-1-phosphate (S1P), and acid ceramidase is positioned as a ceramide rheostat.

The document describes using engineered viral vector Anc80 to express sphingolipid-metabolizing proteins, including acid ceramidase, in mammalian cells to reduce ceramide and mitigate cell death and/or senescence. It further describes related targets within sphingolipid pathways and signaling, including sphingosine kinase (Sphk1) and S1PR2, as well as other sphingolipid-metabolizing proteins such as CERK and ceramidases.

The document compares Anc80 with AAV for sustained or higher expression and reduced cross-reactivity, and it provides supported protein targets and sequence references for ceramidase genes and Anc80 encoding sequences. The disclosed preclinical observations include MI-associated gene/protein expression dynamics involving acid ceramidase (AC) subunits and AC activity and changes in Sphk1 and S1PR2, along with vector expression and biodistribution studies in rodents and therapeutic rescue in sheep following AC-Anc80 gene delivery, including cardiac MRI and functional outcomes.

Claims Coverage

The partial content provides one independent claim. The independent claim includes an Anc80 viral vector carrying an operatively linked acid ceramidase-encoding nucleotide sequence, directly administered in vivo to cardiac cells, with the objective of restoring heart function after ischemia/reperfusion injury or MI.

Across the provided independent claim, the inventive focus is on in vivo delivery of an Anc80 vector that expresses an acid ceramidase protein from an operatively linked nucleotide sequence in cardiac cells to restore heart function after ischemia, reperfusion injury or MI. The dependent claims shown refine the nucleotide sequences by specifying particular acid ceramidase nucleotide sequence options (SEQ ID NOs) or a selected sequence.

Stated Advantages

Documented Applications