METHODS FOR TREATING LYSOSOMAL STORAGE DISEASES
This disclosure provides novel animal models for use in studying lysosomal storage diseases and methods of treating lysosomal storage diseases by increasing a level or activity of TPP1.
1 . A method of treating a subject having a disease or disorder characterized by accumulation of SCMAS in the lysosomes of affected cells, comprising administering to the subject a therapeutically effective amount of an agent that increases a level or activity of TPP1, to reduce or eliminate symptoms caused by the disease or disorder.
2 . The method of claim 1 , wherein the disease or disorder is selected from Juvenile neuronal ceroid lipofuscinosis (CLN3) disease, Variant late infantile neuronal ceroid lipofuscinosis type 5 (CLN5) disease, Variant late infantile neuronal ceroid lipofuscinosis type 6 (CLN6) disease, Neuronal ceroid lipofuscinosis type 7 (CLN7) disease, Northern epilepsy neuronal ceroid lipofuscinosis type 8 (CLN8) disease, Congenital neuronal ceroid lipofuscinosis type 10 (CLN10) disease, Late-onset Neuronal ceroid lipofuscinosis (CLN12) and Kufor-Rakeb syndrome, Sanfilippo D syndrome (mucopolysaccharidosis type HID), and Osteopetrosis autosomal recessive 4 (OPTB4).
3 . The method of any one of the preceding claims , wherein the disease or disorder is characterized by a deficiency in a function of a CLN3 protein.
4 . The method of any one of the preceding claims , wherein the agent reduces the level of accumulation of the SCMAS in the lysosomes of the affected cells.
5 . The method of any one of the preceding claims , wherein the affected cells are neuronal cells.
6 . The method of any one of the preceding claims , wherein the agent comprises a recombinant human TPP1 protein or a nucleic acid molecule comprising a nucleotide sequence encoding TPP1 or a variant thereof.
7 . The method of claim 6 , wherein the TPP1 protein is an inactive proenzyme.
8 . The method of any one of claims 6 to 7 , wherein the TPP1 protein is mannose-6-phosphorylated.
9 . The method of any one of claims 6 to 8 , wherein the therapeutically effective amount of the TPP1 protein is such that the affected cells receive from about 1.0 to about 100 nM of recombinant human TPP1 protein.
10 . The method of any one of claims 6 to 9 , wherein the agent is administered by injection.
11 . The method of any one of claim 10 , wherein the injection is intracranial.
12 . The method of any one of the preceding claims , wherein the agent is administered in a controlled release system.
13 . The method of any one of the preceding claims , wherein the agent is delivered to lysosomes of the affected cells.
14 . The method of any one of the preceding claims , wherein the subject is a human.
15 . An animal model for studying a disease or disorder, comprising: (i) a tripeptidyl peptidase 1 (Tpp1) gene heterozygous knockout (Tpp1 +/− ); and (ii) a Cln3 gene homozygous knockout (Cln3 −/− ), wherein the mouse model has a shortened lifespan compared to a wild type animal.
16 . The animal model of claim 15 , wherein the animal is a mouse.
17 . The animal model of any one of claims 15 to 16 , wherein the disease or disorder is selected from Late-infantile neuronal ceroid lipofuscinosis (CLN2) disease, Juvenile neuronal ceroid lipofuscinosis (CLN3) disease, Variant late infantile neuronal ceroid lipofuscinosis type 5 (CLN5) disease, Variant late infantile neuronal ceroid lipofuscinosis type 6 (CLN6) disease, Neuronal ceroid lipofuscinosis type 7 (CLN7) disease, Northern epilepsy neuronal ceroid lipofuscinosis type 8 (CLN8) disease, Congenital neuronal ceroid lipofuscinosis type 10 (CLN10) disease, Late-onset Neuronal ceroid lipofuscinosis (CLN12) and Kufor-Rakeb syndrome, Sanfilippo D syndrome (mucopolysaccharidosis type HID), and Osteopetrosis autosomal recessive 4 (OPTB4).
18 . The animal model of any one of claims 15 to 17 , wherein the animal has at least 25% reduction in lifespan compared to the wild type animal.
19 . The animal model of any one of claims 15 to 18 , wherein the Tpp1 gene or the Cln3 gene comprises at least one mutation selected from a deletion, an insertion, a frame-shift mutation, re-arrangement or a substitution.
20 . The animal model of claim 19 , wherein the mutation is constitutive.
21 . The animal model of claim 19 , wherein the mutation is conditional.
22 . The animal model of any one of the preceding claims , wherein the Tpp1 gene comprises a deletion of at least a portion of an exon within the Tpp1 gene.
23 . The animal model of any one of claims 15 to 22 , wherein the Tpp1 gene comprises an insertion of neo into intron 11 and an Arg446His missense mutation into exon 11 immediately upstream of the neo insertion.
24 . The animal model of any one of claims 15 to 23 , wherein the Tpp1 gene is located at Chr 7 E3; 7 55.97 cM.
25 . The animal model of any one of claims 15 to 24 , wherein the Cln3 gene comprises a deletion of at least a portion of an exon within the Cln3 gene.
26 . The animal model of any one of claims 15 to 25 , wherein the Cln3 gene comprises a deletion of all or part of exons 1-6 within the Cln3 gene.
27 . The animal model of any one of claims 15 to 26 , wherein the Cln3 gene is located at Chr 7 F3; 7 69.16 cM.
28 . The animal model of any one of claims 15 to 27 , wherein the animal model has an increased level of lysosomal accumulation of subunit c of mitochondrial ATP synthase (SCMAS).
29 . The animal model of claim 28 , wherein the animal model has at least 50% increase in the level of lysosomal accumulation of SCMAS.
30 . The animal model of any one of claims 15 to 29 , wherein the animal model has an increased expression level of Niemann-Pick disease type C1 (NPC1) and/or Cathepsin F (CTSF) or reduced expression of SMPD1.
31 . The animal model of claim 30 , wherein the animal model has at least 40% increase in the expression level of NPC1 and/or CTSF or 40% decrease in the expression level of acid sphingomyelinase (SMPD1).
32 . The animal model of any one of claims 15 to 31 , wherein the animal model is characterized by a deficit in a locomotor activity.
33 . A progeny of the animal model of any one of claims 15 to 32 .
34 . A cell, tissue, or cell line derived from the animal model of any one of claims 15 to 32 or the progeny of claim 33 .
35 . A method of obtaining the animal model of any one of claims 15 to 32 , comprising: (a) cross-breeding an animal with a Tpp1 knockout with a second animal with a Cln3 knockout to obtain an animal with double heterozygotes (Tpp1 +/− ; Cln3 +/− ); and (b) cross-breeding the animal with double heterozygotes by mating Tpp1 −/− ; Cln3 −/− ×Tpp1 −/− ; Cln3 −/− or Tpp1 −/− ; Cln3 −/+ ×Tpp1 +/− ; Cln3 −/− .
36 . A method of identifying an agent for use in treatment of a disease or disorder in a subject, comprising:
(i) administering a candidate agent to the animal model of any one of claims 15 to 32 or the progeny of claim 33 , and assessing an effect of the candidate agent on a phenotype of the animal model; or
(ii) contacting the cell, tissue, or cell line of claim 34 with a candidate agent, and assessing an effect of the candidate agent on the cell, tissue, or cell line.
37 . The method of claim 36 , wherein the disease or disorder is characterized by accumulation of SCMAS in the lysosomes of affected cells of the animal model.
38 . The method of any one of claims 36 to 37 , wherein the disease or disorder is selected from Late-infantile neuronal ceroid lipofuscinosis (CLN2) disease, Juvenile neuronal ceroid lipofuscinosis (CLN3) disease, Variant late infantile neuronal ceroid lipofuscinosis type 5 (CLN5) disease, Variant late infantile neuronal ceroid lipofuscinosis type 6 (CLN6) disease, Neuronal ceroid lipofuscinosis type 7 (CLN7) disease, Northern epilepsy neuronal ceroid lipofuscinosis type 8 (CLN8) disease, Congenital neuronal ceroid lipofuscinosis type 10 (CLN10) disease, Late-onset Neuronal ceroid lipofuscinosis (CLN12) and Kufor-Rakeb syndrome, Sanfilippo D syndrome (mucopolysaccharidosis type HID), and Osteopetrosis autosomal recessive 4 (OPTB4).
39 . The method of claims 36 to 38 , wherein the phenotype is a lifespan of the animal model.
40 . The method of any one of claims 36 to 39 , wherein the effect is characterized by an increase in the lifespan of the animal model.
41 . The method of any one of claims 36 to 40 , wherein the effect is characterized by a decrease in the level of lysosomal accumulation of SCMAS.
42 . The method of any one of claims 36 to 41 , wherein the effect is characterized by a decrease in the expression level of NPC1 and/or CTSF.
43 . The method of any one of claims 36 to 42 , wherein the candidate agent comprises a protein, a peptide, a peptidomimetic, a nucleic acid, or a small molecule.