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US-20260124320-A1 - FORMULATIONS FOR AAV GENE THERAPY

US20260124320A1US 20260124320 A1US20260124320 A1US 20260124320A1US-20260124320-A1

Abstract

Compositions for the storing and maintaining virus viability including a balance of ionic strength and osmolality, which lead to reproducible and stable product quality at room temperature, at 4° C., and have the ability to withstand 10 freeze/thaw events.

Inventors

  • Jayan SENARATNE
  • Greta JASULAITYTE

Assignees

  • MEIRAGTX UK II LIMITED

Dates

Publication Date
20260507
Application Date
20231011

Claims (20)

  1. 1 . A cryoprotective formulation for storing, maintaining infectivity, and/or maintaining viability of adeno-associated virus (AAV) particles, the formulation comprising a saccharide, a salt, a buffer, a surfactant, or combinations thereof.
  2. 2 . A pharmaceutical composition for storing, maintaining infectivity, and/or maintaining viability of AAV particles comprising a saccharide, a salt, a buffer, a surfactant, or combinations thereof.
  3. 3 . The cryoprotective formulation of claim 1 or the pharmaceutical composition of claim 2 , wherein the saccharide comprises one or more saccharides.
  4. 4 . The cryoprotective formulation of claims 1 or 3 or the pharmaceutical composition of claims 2 or 3 , wherein the one or more saccharides comprise trehalose, cyclodextrin, sucrose, or combinations thereof.
  5. 5 . The cryoprotective formulation or the pharmaceutical composition of claim 3 , wherein the saccharide is cyclodextrin.
  6. 6 . The cryoprotective formulation or the pharmaceutical composition of claim 5 , wherein the cyclodextrin is at a concentration of about 0.1% weight/volume (w/v) up to about 20% (w/v).
  7. 7 . The cryoprotective formulation or the pharmaceutical composition of claim 6 , wherein the cyclodextrin is at a concentration of about 0.1% (w/v) up to about 1% (w/v).
  8. 8 . The cryoprotective formulation or the pharmaceutical composition of claim 7 , wherein the cyclodextrin is at a concentration of about 0.4% (w/v).
  9. 9 . The cryoprotective formulation or the pharmaceutical composition of claim 3 , wherein the saccharide is trehalose.
  10. 10 . The cryoprotective formulation or the pharmaceutical composition of claim 9 , wherein the trehalose is at a concentration of about 0.5% (w/v) to about 20% (w/v).
  11. 11 . The cryoprotective formulation or the pharmaceutical composition of claim 10 , wherein the trehalose is at a concentration of about 0.5% (w/v) to about 5% (w/v).
  12. 12 . The cryoprotective formulation or the pharmaceutical composition of claim 11 , wherein the trehalose is at a concentration of about 1.1% (w/v).
  13. 13 . The cryoprotective formulation of any one of claims 1, or 3-12 or the pharmaceutical composition of claims 2-12 , wherein the salt comprises a sodium salt, a magnesium salt, a calcium salt, a potassium salt, a phosphate salt; a sulfate salt, triethylamine, guanidine, N-substituted guanidine salts, acetamidine, N-substituted acetamidine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine or N,N′-dibenzylethylenediamine salts, or combinations thereof.
  14. 14 . The cryoprotective formulation or the pharmaceutical composition of claim 13 , wherein the salt is a sodium salt, a magnesium salt, a calcium salt, a potassium salt, a phosphate salt, a sulfate salt or combinations thereof.
  15. 15 . The cryoprotective formulation or the pharmaceutical composition of claim 14 , wherein the salt is a sodium salt.
  16. 16 . The cryoprotective formulation or the pharmaceutical composition of claim 15 , wherein the sodium salt is sodium chloride, sodium phosphate, or both.
  17. 17 . The cryoprotective formulation or the pharmaceutical composition of claim 16 , wherein the sodium chloride is at a concentration of about 100 mM to about 400 mM.
  18. 18 . The cryoprotective formulation or the pharmaceutical composition of claim 17 , wherein the sodium chloride is at a concentration of about 200 mM to about 350 mM.
  19. 19 . The cryoprotective formulation or the pharmaceutical composition of claim 18 , wherein the sodium chloride is at a concentration of about 280 mM.
  20. 20 . The cryoprotective formulation or the pharmaceutical composition of claim 14 , wherein the salt is a magnesium salt.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of the earlier filing date of U.S. Provisional Patent Application No. 63/379,117, filed Oct. 11, 2022, which is hereby incorporated by reference in its entirety. FIELD The present disclosure relates to formulations for storing and maintaining the viability or infectivity of adeno-associated virus (AAV) following freeze-thawing cycles. BACKGROUND AAV gene therapies in a liquid formulation are rarely considered stable under refrigeration and are typically stabilized through freezing at −80° C. However, the process of freezing and thawing may compromise product quality, while transportation and storage of frozen materials is often complicated and expensive. Furthermore, the use of freezing at −80° C. reduces the number of available drug delivery device options, e.g., pre-filled syringes, which can hinder accessibility of the product. As such, new formulations for storing and maintaining viability/infectivity of AAV gene therapy products are urgently needed. SUMMARY Embodiments of this disclosure are directed to formulations that maintain AAV product quality at various storage temperatures, from about ambient temperature including up to −80° C., and/or exposure to multiple freeze/thaw conditions over time. Accordingly, in certain aspects, provided is a formulation for an AAV particle, wherein the formulation comprises a saccharide, a buffer, a surfactant, a salt or combinations thereof. In certain embodiments, the saccharide comprises one or more saccharides. In certain embodiments, the one or more saccharide comprise trehalose, cyclodextrin, sucrose or combinations thereof. In certain embodiments, the salt comprises a sodium salt, a magnesium salt, a calcium salt, a potassium salt, a phosphate salt, a sulfate salt, triethylamine, guanidine, N-substituted guanidine salts, acetamidine, N-substituted acetamidine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine or N,N′-dibenzylethylenediamine salts, or combinations thereof. In certain embodiments, the sodium salt comprises sodium chloride, sodium phosphate, or the combination thereof. In certain embodiments, the magnesium salt is magnesium sulfate. In certain embodiments, the salt comprises sodium chloride, sodium phosphate, magnesium sulfate or the combination thereof. In certain embodiments, the formulation further comprises a buffer, comprising phosphate buffered saline (PBS) sodium phosphate, citric acid, acetic acid, tromethamine, aspartic acid, glutamic acid, HEPES, Tris, Bicine, acetate, glutamate, lactate, maleate, tartrate, phosphate, citrate, carbonate, glycinate, histidine, glycine, lysine, arginine, succinate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MOPS (3-(N-morpholino) propanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), triethanolamine buffer, and combinations thereof. In certain embodiments, the surfactant is a non-ionic surfactant. In certain embodiments, the non-ionic surfactant comprises a polysorbate. In certain embodiments, the polysorbate is polysorbate 80. In certain embodiments, the formulation comprises an ionic strength from about 100 mM to about 700 mM. In certain embodiments, the formulation comprises an osmolality (mOsm/kg) from about 100 mOsm/kg to about 800 mOsm/kg. In certain embodiments, the formulation comprises a pH of about 7.0 to about 8.0. In certain embodiments, the formulation comprises a pH of about 7.5. In certain embodiments, the formulation is utilized for storing or maintaining viability of adeno-associated virus (AAV) particles over periods of time at temperatures from about 20° C. to about −80° C. In certain embodiments, the AAV particles are stable over multiple freeze-thawing cycles. In certain embodiments, the AAV particles are derived from an AAV with an AAV serotype selected from serotypes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, DJ or DJ/8. In certain embodiments, the AAV particle comprises a genome derived from AAV serotype 2. In certain embodiments, the AAV particles comprise a capsid derived from AAV serotype 2. In another aspect, a pharmaceutical composition for storing, maintaining infectivity, and/or maintaining viability of AAV particles comprises a cryoprotectant, a buffer, a surfactant and a salt. In certain embodiments, the cryoprotectant comprises one or more saccharides. In certain embodiments, the saccharides comprise trehalose, cyclodextrin, sucrose or combinations thereof. In certain embodiments, the salt comprises a sodium salt, a magnesium salt, a calcium salt, a potassium salt, a phosphate salt, a sulfate salt or combinations thereof. In certain embodiments, the sodium salt comprises sodium chloride, sodium phosphate or the combination thereof. In certain embodiments, the magnesium salt is magnesium sulfate. In certain embodiments, the surfactant is a non-ionic surfactant. In certain embodiments, the non-ionic surfactant compri