Compositions and methods for treating retinal disorders
The present invention relates to the prevention and/or treatment of retinal disorders, such as cone dystrophies, cone-rod dystrophies, in particular Achromatopsia.
1 . A transcriptional control unit (TCU) of up to 2500 nucleotides in length comprising in a 5′ to 3′ direction:
(a) a Locus Control Region (LCR) comprising SEQ ID NO: 1, and
(b) a promoter element comprising SEQ ID NO: 3.
2 . An expression construct comprising the TCU of claim 1 , wherein the TCU is operably linked to a gene sequence to be expressed.
3 . The expression construct according to claim 2 , wherein the operably linked gene sequence is CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, KCNV2 or CACNA2D4.
4 . The expression construct according to claim 3 , wherein the operably linked gene sequence has at least 80% sequence identity to SEQ ID NO: 7, 8, 9, 10, 11, 12, 13 or 14.
5 . The expression construct according to claim 4 , wherein the operably linked gene sequence comprises SEQ ID NO: 7, 8, 9, 10, 11, 12, 13 or 14.
6 . The expression construct according to claim 4 , wherein the operably linked gene sequence has at least 80% sequence identity to SEQ ID NO: 8.
7 . The expression construct according to claim 6 , wherein the operably linked gene sequence comprises SEQ ID NO: 8.
8 . A vector comprising the expression construct according to claim 2 .
9 . The vector according to claim 8 , wherein the vector is a viral vector.
10 . The vector according to claim 9 , wherein the vector is an adeno-associated virus (AAV) vector.
11 . The vector of claim 10 , wherein the AAV vector comprises an AAV genome derivative, wherein the derivative is a chimeric, shuffled or capsid modified derivative.
12 . The vector of claim 10 , wherein the AAV vector comprises an AAV genome from a naturally derived serotype or isolate or clade of AAV.
13 . The vector of claim 12 , wherein said AAV genome is derived from AAV serotype 2 (AAV2), AAV serotype 4 (AAV4), or AAV serotype 8 (AAV8).
14 . The vector of claim 13 , wherein the AAV genome is derived from AAV2.
15 . The vector of claim 10 , wherein the AAV vector comprises a capsid that is derived from AAV8.
16 . An isolated host cell that contains the vector of claim 8 .
17 . The isolated host cell of claim 16 , wherein the cell is a HEK293 or HEK293T cell.
18 . A pharmaceutical composition comprising the vector of claim 8 and a pharmaceutically acceptable carrier.
19 . A method of treating a retinal disorder in a patient in need thereof, comprising administering a therapeutically effective amount of the vector according to claim 8 to said patient.
20 . The method of claim 19 , wherein the retinal disorder is Achromatopsia.
21 . The method of claim 19 , wherein the treatment is by administration of the vector to the patient by direct retinal, subretinal, or intravitreal injection.
22 . The method according to claim 19 , wherein said vector is administered directly into the retinal, subretinal space, or intravitreal space.
23 . The TCU of claim 1 , wherein the TCU comprises SEQ ID NO: 15.
24 . An expression construct comprising the TCU of claim 23 , wherein the TCU is operably linked to a gene sequence to be expressed.
25 . The expression construct according to claim 24 , wherein the operably linked gene sequence is CNGA3.
26 . The expression construct according to claim 25 , wherein the operably linked gene sequence comprises SEQ ID NO: 8.
27 . An AAV vector comprising the expression construct according to claim 26 .
28 . The vector of claim 27 , wherein the AAV vector comprises an AAV genome derived from AAV2.
29 . The vector of claim 28 , wherein the AAV comprises a capsid that is derived from AAV8.