Therapeutics for glycogen storage disease type III
Inventors
Tachikawa, Kiyoshi • PEREZ-GARCIA, Carlos Gustavo • Chivukula, Padmanabh • Bhaskaran, Hari • COBAUGH, Christian W. • DAUGHERTY, Sean Christopher
Assignees
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Publication Number
US-11377643-B2
Publication Date
2022-07-05
Expiration Date
Abstract
This invention provides a range of translatable polynucleotide and oligomer molecules for expressing a human amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL), or a fragment thereof having AGL activity. The polynucleotide and oligomer molecules are expressible to provide the human AGL or a fragment thereof having AGL activity. The molecules can be used as active agents to express an active polypeptide or protein in cells or subjects. The agents can be used in methods for ameliorating, preventing, delaying onset, or treating a disease or condition associated with reduced activity of amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) in a subject.
Core Innovation
The disclosure provides a translatable polynucleotide and translatable oligomer therapeutic framework for expressing human amylo-alpha-1,6-glucosidase, 4-alpha-glucanotransferase (hAGL). In particular, the polynucleotide includes a nucleobase sequence encoding hAGL of SEQ ID NO: 2, with the nucleobase sequence encoding hAGL being at least 99% identical to sequences selected from SEQ ID NOs: 7-32 and SEQ ID NOs: 41-45. The described nucleic acid architecture includes a 5′ cap, 5′ and/or 3′ UTRs, a coding region, and a tail/polyA configuration.
The invention further specifies functional transcript and sequence features intended to increase cytoplasmic and/or functional half-life and translation efficiency. The disclosure includes nucleotide modifications, including replacing uridine residues with N1-methylpseudouridine residues, and defines optional or specific UTR selections and polyA tail configurations. Internal ribosome entry site concepts, capped translation features, and UNA-based oligomer structures and linkers using unlocked nucleic acid concepts are also mentioned.
The therapeutic approach is described for expression in cells and subjects, including delivering the translatable polynucleotide via lipid formulations. The disclosure mentions delivery using lipid nanoparticles and liposomes, including cationic lipid selections within nanoparticles. The document indicates evaluation of translatable AGL molecules in vitro and in vivo, with treatment directed to glycogen storage disease type III (GSD III) and related AGL deficiency.
Claims Coverage
The independent claim clm-00001 covers a polynucleotide encoding human hAGL with specified SEQ ID relationships and at least 99% sequence identity constraints. The claim set includes dependent refinements that add transcript element constraints, nucleotide modifications, defined UTR sequences, carrier composition features, and an explicit therapeutic use for glycogen storage disease type III via administration.
Human hAGL-encoding polynucleotide with defined SEQ ID identity
A polynucleotide comprising a nucleobase sequence encoding a human amylo-alpha-1,6-glucosidase, 4-alpha-glucanotransferase (hAGL) of SEQ ID NO: 2, wherein the nucleobase sequence encoding hAGL is at least 99% identical to a sequence selected from SEQ ID NOs: 7-32 and SEQ ID NOs: 41-45.
Full N1-methylpseudouridine substitution of uridine residues
The polynucleotide is modified so that every uridine residue is replaced with N1-methylpseudouridine residues.
Defined 5′ UTR sequence
The polynucleotide has a 5′ UTR comprising SEQ ID NO: 3.
Defined 3′ polyA tail length range
The polynucleotide has a 3′ polyA tail that is 60 to 220 adenosine nucleotides long.
Nanoparticle with specified cationic lipid selection
A nanoparticle that includes a cationic lipid selected from ATX-002, ATX-081, ATX-095, and ATX-126.
Treatment of glycogen storage disease type III by administration
A method for treating glycogen storage disease type III in a subject by administering the composition.
Across the claims described, the core inventive coverage centers on an hAGL-encoding translatable polynucleotide constrained by SEQ ID identity and further refined by defined transcript element features, full N1-methylpseudouridine substitution, and nanoparticle/carrier definitions, culminating in treatment of glycogen storage disease type III by administration of the composition.
Stated Advantages
Increased liver AGL expression.
Reduced AGL markers such as ALT/AST/CPK.
Reduced glycogen and limit dextrin-related measures in the glycogen storage disease type III context.
Improved cytoplasmic/functional half-life.
Increased translation efficiency versus native mRNA.
Potential reduced dosing.
Documented Applications
Treatment of glycogen storage disease type III in a subject by administering a composition comprising the hAGL-encoding polynucleotide.
Expression of translatable AGL molecules in vitro (including in cells) and in vivo (including liver AGL expression in mice).
Treatment application directed to glycogen storage disease type III (GSD III) and related AGL deficiency in a subject by administration of the composition.
Histopathology improvements in AGL knockout mice associated with the described AGL therapeutic approach.
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