US 2025/0049955 A1Published application

Compositons and methods for the treatment of neurological disorders related to glucosylceramidase beta deficiency

AssigneeVoyager Therapeutics, Inc.

InventorsMathieu Emmanuel NONNENMACHER, Matthew Alan CHILD, Jinzhao HOU, Jiangyu LI, Shaoyong LI, Tyler Christopher MOYER, Wei WANG, Giridhar MURLIDHARAN, Kelly BALES, Jeffrey BROWN, Elisabeth KNOLL, Smita JAGTAP, Yanqun SHU, Adewale ADELUYI, Brett HOFFMAN, Nilesh Navalkishor PANDE, Jeffrey Scott THOMPSON

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Abstract

The disclosure relates to compositions and methods for altering, e.g., enhancing, the expression of GCase proteins, whether in vitro and/or in vivo. Such compositions include delivery of an adeno-associated viral (AAV) particle. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, or suspected of having Parkinson Disease or related condition resulting from a deficiency in the quantity and/or function of GBA gene product or associated with decreased expression or protein levels of GCase protein.

Claims55

Dependent claims

An isolated, e.g., recombinant, AAV particle comprising an AAV capsid variant and a nucleic acid comprising a transgene encoding a β-glucocerebrosidase (GBA) protein comprising the amino acid sequence of SEQ ID NO:

1775, or an amino acid sequence at least 85% (e.g., at least 90%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO:
1775, wherein the AAV capsid variant comprises an amino sequence comprising the following formula:
[N1]-[N2], wherein:
(i) [N1] comprises X1, X2, X3, X4, and X5, wherein:
(a) position X1 is:
P, Q, A, H, K, L, R, S, or T;
(b) position X2 is:
L, I, V, H, or R;
(c) position X3 is:
N, D, I, K, or Y;
(d) position X4 is:
G, A, C, R, or S;
and
(e) position X5 is:
A, S, T, G, C, D, N, Q, V, or Y;
and
(ii) [N2] comprises the amino acid sequence of VHLY, VHIY, VHVY, or VHHY;
and/or a substitution, e.g., a conservative substitution, of any of the aforesaid amino acids in (i) and/or (ii);
wherein [N1]-[N2] is present from N-terminus to C-terminus, immediately subsequent to position 586, numbered according to any one of SEQ ID NO:
5, 8, 138, or 3636;
optionally, wherein the AAV capsid variant comprises:
(a) an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-743, e.g., a VP3, of any one of SEQ ID NO:
5, 8, or 3636;
or
(b) an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736, e.g., a VP3, of SEQ ID NO:
138.

23 more elements

1775, or an amino acid sequence at least 85% (e.g., at least 90%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO:
1775, wherein the AAV capsid variant comprises [A][B], wherein [A] comprises the amino acid sequence of PLNGA, and [B] comprises X1, X2, X3, X4, wherein:
(i) X1 is:
V, I, L, A, F, D, or G;
(ii) X2 is:
H, N, Q, P, D, L, R, or Y;
(iii) X3 is:
L, H, I, R, or V;
and
(iv) X4 is Y;
and/or
wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i)-(iv);
wherein [A][B] is present from N-terminus to C-terminus, immediately subsequent to position 586, numbered according to any one of SEQ ID NO:
5, 8, 138, or 3636;
optionally wherein the AAV capsid variant comprises:
(a) an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-743, e.g., a VP3, of any one of SEQ ID NO:
5, 8, or 3636;
or
(b) an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736, e.g., a VP3, of SEQ ID NO:
138.

17 more elements

1775, or an amino acid sequence at least 85% (e.g., at least 90%, 95%, 96%, 97%, 98%, or 99%) identical to SEQ ID NO:
1775, wherein the AAV capsid variant comprises:
(i) the amino acid sequence of PLNGAVHLY (SEQ ID NO:
3648);
(ii) an amino acid sequence comprising at least 5, 6, 7, 8, or 9 consecutive amino acids from the amino acid sequence of PLNGAVHLY (SEQ ID NO:
3648);
(iii) an amino acid sequence comprising at least one, two, or three but no more than four substitutions (e.g., conservative substitutions), relative to the amino acid sequence of PLNGAVHLY (SEQ ID NO:
3648);
or
(iv) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of PLNGAVHLY (SEQ ID NO:
3648)
wherein the amino acid sequence of (i)-(iv) is present immediately subsequent to position 586, numbered according to any one of SEQ ID NOs:
5, 8, 138, or 3636;
optionally wherein the AAV capsid variant further comprises:
(a) a VP1 protein comprising the amino acid sequence of SEQ ID NO:
5, 8, 3636;
(b) a VP2 protein comprising the amino acid sequence of positions 138-743 of SEQ ID NO:
5, 8, or 3636;
(c) a VP3 protein comprising the amino acid sequence of positions 203-743 of SEQ ID NO:
5, 8, or 3636;
or
(d) an amino acid sequence at least 90% (e.g., at least 92%, 95%, 96%, 97%, 98%, or 99%) identical to any one the amino acid sequences of (a)-(b).

19 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/711,069Filed 16 Nov 2022
Priority: 17 Nov 2021
Published: 13 Feb 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

A61K 48/0058
Characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered: nucleic acids adapted for tissue…
C07K 14/005
Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof: from viruses
A61K 38/50
Hydrolases: acting on carbon-nitrogen bonds, other than peptide bonds , e.g. asparaginase
A61K 48/005
Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy:…

Family

Application63/280,480Us provisional application · filed 17 Nov 2021
US 2025/0049955 A1This patent

From the US filing history. Foreign family members aren’t listed.

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