IP Library › Granted Patent US 11,273,227
Granted Patent B2
US 11,273,227 · App. 15/766,973 · Granted Mar 15, 2022

Compositions and methods useful in treating Stargardt's disease and other ocular disorders

Inventor: Kathleen Boesze-Battaglia (Haddon Heights, NJ)
Assignee: The Trustees of the University of Pennsylvania
A61K48/0058A61K9/0048A61K38/1709A61K48/005A61K48/0075C07K14/47C12N15/86A61K38/00A61K2039/515C12N2750/14143C12N2830/15
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Quick Facts
Patent No.
US 11,273,227
App. No.
15/766,973
Granted
Mar 15, 2022
Kind
B2
Abstract

Engineered MREG proteins are described. Further described are viral vectors expressing native or engineered MREG proteins. Further described are compositions containing these vectors or proteins formulated for delivery to the eye. Also provided are methods for delivering these native and engineered MREG proteins to ocular cells for treatment of Stargardt's disease, macular degeneration and other ocular disorders.

Claims (87)

1. A recombinant adeno-associated viral (rAAV) vector useful in treating a subject with age-related macular degeneration and/or Stargardt's Disease which comprises an AAV capsid and a nucleic acid molecule packaged therein, wherein the nucleic acid molecule comprises a 5′ AAV inverted terminal repeat (ITR) sequence, a nucleic acid sequence encoding a mutated melanoregulin (MREG) protein under the control of expression control sequences which direct expression of the mutated MREG protein in ocular cells of the subject's eye, and a 3′ AAV ITR sequence, wherein the mutated MREG protein is:

(a) MREG USΔ10: SEQ ID NO: 57:

N -CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFKLARRTY PKKPGVPCLA

DGQK ELHYLP FPSP- C ,

(b) MREG USΔ20: SEQ ID NO: 58:

N -ERALPEKEPL VSDNNPYSSF GATLVRDDEK

NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ AKDSEEWQKL

NYDIHTLRQV RREVRNRWKC ILEDLGFQKE ADSLLSVTKL

STISDSKNTR KAREMLLKLA EETNIFPTSW ELSERYLFVV

DRLIALDAAE EFFKLARRTY PKKPGVPCLA DGQKELHYLP

FPSP- C ,

(c) MREG USΔ30: SEQ ID NO: 59:

N -VSDNNPYSSF GATLVRDDEK NLWSMPHDVS

HTEADDDRTL YNLIVIRNQQ AKDSEEWQKL NYDIHTLRQV

RREVRNRWKC ILEDLGFQKE ADSLLSVTKL STISDSKNTR

KAREMLLKLA EETNIFPTSW ELSERYLFVV DRLIALDAAE

EFFKLARRTY PKKPGVPCLA DGQKELHYLP FPSP- C .

(d) MREG DSΔ10: SEQ ID NO: 60:

N -CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFKLARRTY PKKP

GVPCLA DGQK- C ,

(e) MREG DSΔ20: SEQ ID NO: 61:

N -CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFKLARRTY PKKP- C ,

or

(f) MREG DSΔ30: SEQ ID NO: 62:

N -CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFK- C .

2. The rAAV according to claim 1 , wherein the 5′ and 3′ ITR sequences are self-complementary ITRs.

3. The rAAV according to claim 1 , wherein the ITRs are from a different AAV source than the AAV capsid.

4. The rAAV according to claim 1 , wherein the AAV capsid is selected from AAV1, AAV5, or AAV8.

5. A composition for delivery to the eye comprising the rAAV according to claim 1 and a pharmaceutically acceptable vehicle, excipient or carrier.

6. The composition according to claim 5 , wherein the composition comprises about 1.5×10 9 genome copies/mL to about 1.5×10 12 genome copies/mL.

7. A composition comprising at least one engineered MREG protein and a pharmaceutically acceptable carrier and/or excipient, wherein the engineered MREG is:

(a) MREG USΔ10: SEQ ID NO: 57:

N-CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFKLARRTY PKKPGVPCLA

DGQK ELHYLP FPSP-C,

(b) MREG USΔ20: SEQ ID NO: 58:

N-ERALPEKEPL VSDNNPYSSF GATLVRDDEK

NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ AKDSEEWQKL

NYDIHTLRQV RREVRNRWKC ILEDLGFQKE ADSLLSVTKL

STISDSKNTR KAREMLLKLA EETNIFPTSW ELSERYLFVV

DRLIALDAAE EFFKLARRTY PKKPGVPCLA DGQKELHYLP

FPSP-C,

(c) MREG USΔ30: SEQ ID NO: 59:

N-VSDNNPYSSF GATLVRDDEK NLWSMPHDVS

HTEADDDRTL YNLIVIRNQQ AKDSEEWQKL NYDIHTLRQV

RREVRNRWKC ILEDLGFQKE ADSLLSVTKL STISDSKNTR

KAREMLLKLA EETNIFPTSW ELSERYLFVV DRLIALDAAE

EFFKLARRTY PKKPGVPCLA DGQKELHYLP FPSP-C.

(d) MREG DSΔ10: SEQ ID NO: 60:

N-CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFKLARRTY PKKP

GVPCLA DGQK-C,

(e) MREG DSΔ20: SEQ ID NO: 61:

N-CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFKLARRTY PKKP-C,

and

(f) MREG DSΔ30: SEQ ID NO: 62:

N-CCCCGCECLE ERALPEKEPL VSDNNPYSSF

GATLVRDDEK NLWSMPHDVS HTEADDDRTL YNLIVIRNQQ

AKDSEEWQKL NYDIHTLRQV RREVRNRWKC ILEDLGFQKE

ADSLLSVTKL STISDSKNTR KAREMLLKLA EETNIFPTSW

ELSERYLFVV DRLIALDAAE EFFK-C.

Assignments (2)
CONFIRMATORY LICENSE Recorded Feb 20, 2019
From: UNIVERSITY OF PENNSYLVANIA
To: NATIONAL INSTITUTES OF HEALTH-DIRECTOR DEITR
Reel/Frame 048388/0648 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 30, 2018
From: BOESZE-BATTAGLIA, KATHLEEN
To: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
Reel/Frame 045664/0749 →
Continuity (2)
Provisional Application 62239480 · Oct 9, 2015
Related Publication 20190060487A1 · Feb 28, 2019