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AssigneeTranslate Bio, Inc.
InventorsAnusha Dias, Darshan Parekh, Jeffrey S. Dubins, Christian Cobaugh, Shrirang Karve, Zarna Patel, Sara J. Dunaj, Frank DeRosa, Michael Heartlein
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The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal heavy chain 5 (DNAH5) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAH5 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.
A method of delivery of human axonemal dynein heavy chain 5 (DNAH5) in vivo comprising administering to a subject in need of delivery an mRNA encoding a human DNAH5 protein.
A method of treating primary ciliary dyskinesia (PCD) comprising administering to a subject in need of treatment an mRNA encoding human axonemal dynein heavy chain 5 (DNAH5) at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has delayed in onset.
The method of any one of the preceding claims, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine) DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)) or combinations thereof.
The method of any one of the preceding claims, wherein the cationic lipid constitutes about 30-60% of the liposome by molar ratio.
The method of any one of the preceding claims, wherein the liposome comprises ICE, DOPE and DMG-PEG2K.
The method of any one of the preceding claims, wherein the DNAH5 mRNA is codon optimized.
The method of any one of the preceding claims, wherein the DNAH5 mRNA comprises one or more modified nucleotides.
The method of any one of the preceding claims, wherein the mRNA is unmodified.
The method of any one of the preceding claims, wherein the mRNA comprises a 5′-untranslated region (5′-UTR) that has a sequence set forth in SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a 3′-untranslated region (3′-UTR) that has a sequence set forth in SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a coding sequence at least 70%, 75%, 80%, 85%, 90%, or 95% identical to any one of SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a coding sequence at least 70% identical to SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a coding sequence at least 80% identical to SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a coding sequence at least 90% identical to SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a coding sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:
The method of any one of the preceding claims, wherein the mRNA comprises a coding sequence set forth in SEQ ID NO:
The method of any one of the preceding claims, wherein administering the mRNA to the subject is performed by intratracheal, intranasal, intravenous, intramuscular or subcutaneous delivery.
The method of any one of the preceding claims, wherein administering the mRNA to the subject is performed by intratracheal delivery.
The method of any one of the preceding claims, wherein administering the mRNA to the subject is performed by intranasal delivery.
The method of any one of the preceding claims, wherein the composition is administered once a daily.
The method of any one of the preceding claims, wherein the composition is administered once a week.
The method of any one of the preceding claims, wherein the composition is administered once every two weeks.
The method of any one of the preceding claims, wherein the composition is administered twice a month.
The method of any one of the preceding claims, wherein the composition is administered once a month.
The method of any one of the preceding claims, wherein the administering the mRNA results in DNAH5 protein expression detectable in one or more internal organs selected from lung, heart, liver, spleen, kidney, brain, stomach, intestines, ovary and testis.
The method of any one of the preceding claims, wherein the administering the mRNA results in DNAH5 protein expression detectable in the lung.
The method of any one of the preceding claims, wherein the administering the mRNA results in DNAH5 protein expression detectable in the lung epithelium.
A composition for use in the treatment of primary ciliary dyskinesia (PCD), the composition comprising an mRNA encoding human axonemal dynein heavy chain 5 (DNAH5) encapsulated in a liposome, wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids and one or more PEG-modified lipids.
Dependencies are inferred from the claim text.