US 2006/0218653 A1 · Novel molecular variant and uses thereof

Abstract

The present invention relates to CLN5 nucleic acid and protein variants and functional derivatives, homologues and analogues thereof, together with cellular expression systems, and uses for same. The present invention also provides genetically modified mammalian animals and methods of use thereof. More particularly, the present invention relates to mammalian animals modified to express a mutation in the CLN5 gene, the expression of which variant CLN5 gene induces or otherwise facilitates the onset or progression of a disease condition, and to methods of use thereof. The animals and variant molecules and cells of the present invention are useful in a wide range of applications including, but not limited to, providing a means of diagnosis and means of screening for proteinaceous and non-proteinaceous molecular modulators for use in therapeutic and/or prophylactic applications.

Claims36

Dependent claims

An isolated canine CLN5 protein variant comprising a mutation at amino acid 207 or functionally equivalent residue, wherein said variant exhibits altered functional activity relative to wild-type CLN5 or a derivative, homologue or analogue of said CLN5 variant.

An isolated nucleic acid molecule consisting of:

(i) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence encoding or complementary to a sequence encoding a canine CLN5 variant or derivative or homologue of said variant, which variant comprises a mutation at amino acid 207 or a functionally equivalent residue, wherein said variant exhibits altered functional activity relative to wild-type CLN5;
(ii) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence encoding or complementary to a sequence encoding a canine CLN5 variant or derivative or homologue of said variant, which variant comprises an amino acid sequence with a deletion of glutamine 207 or functionally equivalent residue wherein said variant exhibits altered functional activity relative to wild-type CLN5;
(iii) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence encoding or complementary to a sequence encoding a canine CLN5 variant or derivative or homologue of said variant, which variant comprises an amino acid sequence with Gln207Stop substitution wherein said variant exhibits altered functional activity relative to wild-type CLN5;
(iv) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence encoding or complementary to a sequence encoding a canine CLN5 variant or derivative or homologue of said variant, which variant comprises an amino acid sequence which is truncated at glutamine 207, or functionally equivalent region, of SEQ ID NO:
2, wherein said variant exhibits altered functional activity relative to wild-type CLN5;
(v) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence, or a sequence complementary to said sequence, which sequence comprises a mutation at canine CLN5 C619, or functionally equivalent residue, or a nucleotide sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more identity over a region of at least about 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 residues of said sequence and/or is capable of hybridising to said sequence under low stringency conditions at 42° C.;
(vi) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence, or a sequence complementary to said sequence, which sequence comprises a substitution at canine CLN5 C619, or functionally equivalent residue, or a nucleotide sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more identity over a region of at least about 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 residues of said sequence and/or is capable of hybridising to said sequence under low stringency conditions at 42° C.;
(vii) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence, or a sequence complementary to said sequence, which sequence comprises a canine CLN5 C619T substitution, or functionally equivalent residue, or a nucleotide sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more identity over a region of at least about 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 residues of said sequence and/or is capable of hybridising to said sequence under low stringency conditions at 42° C.;
(viii) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence encoding, or complementary to a sequence, encoding an amino acid sequence substantially as set forth in SEQ ID NO:18 or a derivative or homologue thereof, or an amino acid sequence having at least 50%, 60%, 70%, 80%, 90%, 95%. 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO:18 over a region of 150, 160, 170, 180, 185, 190, 195, 200, 201, 202, 203, 204 or 205 residues of SEQ ID NO:18 and/or is capable of hybridizing to said nucleic acid molecule under low stringency conditions at 42° C.;
(ix) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence encoding, or complementary to a sequence, wherein said nucleotide sequence is substantially as set forth in SEQ ID NO:17 or a nucleotide sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more identity over a region of at least about 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1030, 1040, 1045, 1050, or 1052 residues of SEQ ID NO:17 and/or is capable of hybridising to SEQ ID NO:17 or complementary form thereof under low stringency conditions at 42° C.;
or
(x) an isolated nucleic acid molecule or derivative, homologue or analogue thereof comprising a nucleotide sequence as set forth in SEQ ID NO:17.

9 more elements

A transgenic non-human mammal selected from the list:

(i) a non-human mammal comprising a nucleotide sequence encoding a canine CLN5 variant or derivative or homologue thereof which variant comprises mutation at amino acid 207 or functionally equivalent residue wherein said mammal exhibits aberrant CLN5 functional activity;
(ii) a non-human mammal comprising a nucleotide sequence encoding a canine CLN5 variant or derivative or homologue thereof, which variant comprises an amino acid sequence with a deletion of glutamine 207 or functionally equivalent residue wherein said mammal exhibits aberrant CLN5 functional activity;
(iii) a non-human mammal comprising a nucleotide sequence encoding a canine CLN5 variant or derivative or homologue thereof, which variant comprises an amino acid sequence with a Gln207Stop substitution wherein said mammal exhibits aberrant CLN5 functional activity;
(iv) a non-human mammal comprising a nucleotide sequence encoding a canine CLN5 variant or derivative or homologue thereof, which variant comprises an amino acid sequence which is truncated at glutamine 207 wherein said mammal exhibits a NCL phenotype;
(v) a non-human mammal comprising a nucleotide sequence encoding an amino acid sequence substantially as set forth in SEQ ID NO:18 or a derivative or homologue thereof, or an amino acid sequence having at least 50%, 60%, 70%, 80%, 90%, 95%. 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO:18 over a region of 150, 160, 170, 180, 185, 190, 195, 200, 201, 202, 203, 204 or 205 residues of SEQ ID NO:18 wherein said mammal exhibits aberrant CLN5 functional activity;
(vi) a non-human mammal comprising a nucleotide sequence which sequence comprises a mutation at canine CLN5 C619, or functionally equivalent residue or having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity over a region of 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 of said sequence wherein said mammal exhibits aberrant CLN5 functional activity;
(vii) a non-human mammal comprising a nucleotide sequence which sequence comprises a substitution at canine CLN5 C619, or functionally equivalent residue or having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity over a region of 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 of said sequence wherein said mammal exhibits aberrant CLN5 functional activity;
(viii) a non-human mammal comprising a nucleotide sequence which sequence comprises a canine CLN5 C619T substitution, or functionally equivalent residue or having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity over a region of 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 of said sequence wherein said mammal exhibits aberrant CLN5 functional activity;
(ix) a non-human mammal comprising a nucleotide sequence encoding an expression product wherein said nucleotide sequence is substantially as set forth in SEQ ID NO:17 or a nucleotide sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more identity over a region of at least about 800, 850, 900, 950, 1000, 1010, 1020, 1030, 1040, 1045, 1050 or 1052 residues of SEQ ID NO:17 wherein said mammal exhibits aberrant a NCL phenotype;
or
(x) a non-human mammal comprising a nucleotide sequence substantially as set forth in SEQ ID NO:17 wherein said mammal exhibits a NCL phenotype.

8 more elements

Dependencies are inferred from the claim text.

Novel molecular variant and uses thereof

Life of this patent

Novel molecular variant and uses thereof

Life of this patent

Abstract

Claims36