Protection of Beta Cells from Immune Attack
AssigneeJoslin Diabetes Center, Inc.
InventorsStephan Kissler, Peng Yi
Life of this patent
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Abstract
Compositions of genetically modified beta-like cells are encompassed. Also encompassed are methods of treatment of type 1 diabetes using these compositions or compositions that inhibit the function of the identified genes.
Claims20
A composition comprising a human beta-like cell, wherein the beta-like cell is capable of producing insulin in response to glucose, and wherein the beta-like cell is genetically modified to inhibit expression of one or more of:
- a. menin (SEQ ID No:
- 1);
- b. transcription factor HIVEP2 (SEQ ID No:
- 2);
- c. renalase (SEQ ID No:
- 3);
- d. lengsin (SEQ ID No:
- 4);
- e. eIF-2-alpha kinase activator GCN1 (SEQ ID No:
- 5);
- f. perilipin-4 (SEQ ID No:
- 6);
- g. mediator of RNA polymerase II transcription subunit 11 (SEQ ID No:
- 7);
- h. protein-glutamine gamma-glutamyltransferase 6 (SEQ ID No:
- 8);
- i. zinc finger BED domain-containing protein 3 (SEQ ID No:
- 9);
- and
- j. metabotropic glutamate receptor 2 (SEQ ID No:
- 10).
The composition of any one of the preceding claims, wherein the beta-like cell is a pancreatic beta cell isolated from a human, non-human primate, cow, horse, pig, sheep, goat, dog, cat, or rodent.
The composition of any one of the preceding claims, wherein the beta-like cell is generated from a stem cell.
The composition of any one of the preceding claims, wherein the stem cell is an adult stem cell, pluripotent stem cell, embryonic stem cell, hematopoietic stem cell, bone marrow stromal stem cell, or mesenchymal stem cell.
The composition of any one of the preceding claims, wherein the beta-like cell is a cell that is reprogrammed or transdifferentiated.
The composition of any one of the preceding claims, wherein the reprogrammed or transdifferentiated cell is a pancreatic alpha cell, pancreatic exocrine cell, or a gut or stomach cell.
The composition of any one of the preceding claims, wherein the genetic modification is a substitution, insertion, deletion, or excision of one or more nucleotides.
The composition of any one of the preceding claims, wherein the genetic modification is performed using a CRISPR/Cas9 system, zinc-finger nucleases, transcription activator-like effector nucleases (TALENs), meganucleases, or group one intron encoded endonucleases (GIIEE).
The composition of any one of the preceding claims, wherein the CRISPR/Cas9 system is used with a guide RNA selected from the guide RNAs in Table 2 (SEQ ID Nos:
- 23-35).
The composition of any one of the preceding claims, wherein the genetic modification is within or outside of the coding region of the gene, and wherein no gene product is expressed, or wherein a non-functional gene product is produced.
The composition of any one of the preceding claims, wherein survival or proliferation of the beta-like cells over 1, 2, 3, 4, 5, 6, 12, 18, 24, or 36 months is improved compared to beta-like cells without the genetic modification.
The composition of any one of the preceding claims for use in a method of lowering blood glucose, increasing insulin secretion in response to glucose, treating or ameliorating type 1 diabetes, or preventing the death of pancreatic islet cells in a subject.
The composition of any one of the preceding claims, wherein the subject is a mammal.
The composition of any one of the preceding claims, wherein the mammal is a human.
The composition of any one of the preceding claims, for use with an additional treatment.
The composition of any one of the preceding claims, wherein the additional treatment is insulin, a glucagon-like peptide analog or agonist, dipeptidyl peptidase-4 inhibitor, amylin analog, biguanide, thiazolidinedione, sulfonylurea, meglitinide, alpha-glucosidase inhibitor, or sodium/glucose transporter 2 inhibitor.
The composition of any one of the preceding claims, wherein the composition is administered by transplant into the pancreas, liver, or fat pads via surgery, injection, or infusion.
A method of lowering blood glucose, increasing insulin secretion in response to glucose, treating or ameliorating type 1 diabetes, or preventing the death of pancreatic islet cells in a subject comprising administering a composition that inhibits the function of any one of:
- a. human menin (SEQ ID No:
- 1);
- b. transcription factor HIVEP2 (SEQ ID No:
- 2);
- c. renalase (SEQ ID No:
- 3);
- d. lengsin (SEQ ID No:
- 4);
- e. eIF-2-alpha kinase activator GCN1 (SEQ ID No:
- 5);
- f. perilipin-4 (SEQ ID No:
- 6);
- g. mediator of RNA polymerase II transcription subunit 11 (SEQ ID No:
- 7);
- h. protein-glutamine gamma-glutamyltransferase 6 (SEQ ID No:
- 8);
- i. zinc finger BED domain-containing protein 3 (SEQ ID No:
- 9);
- and
- j. metabotropic glutamate receptor 2 (SEQ ID No:
- 10).
Dependencies are inferred from the claim text.