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Publication Number
US-10760059-B1
Publication Date
2020-09-01
Expiration Date
Abstract
Methods of differentiating unmodified adult stem cells into functional beta-like cells are provided, as well as compositions, tissues and devices containing such cells. The method requires inducing sequential expression of PDX1, NGN3, and MAFA in these stem cells to form reprogrammed beta cells. Methods of treating diabetes are also provided, comprising obtaining stem cells, preferably from a patient with diabetes, inducing sequential expression of PDX1, NGN3, and MAFA, in said stem cells to form reprogrammed beta cells, and introducing said reprogrammed beta cells into a pancreas of said patient. Alternatively, it may be possible to inject such cells systemically, if the cells are targeted for the pancreas. In yet another embodiment, the reprogrammed beta cells are placed into an artificial pancreas that is surgically placed or injected into the patient.
Core Innovation
The invention relates to inducing stem cells to differentiate into beta cells by obtaining a population of unmodified adult somatic stem cells and introducing at least one vector encoding inducible expression of PDX1, NGN3, and MAFA. The method induces sequential expression such that PDX1 is induced before NGN3, and NGN3 is induced before MAFA, using the at least one vector. The induced genes are continuously expressed after being induced, and the stem cells are grown until differentiated beta cells form.
The sequential induction is defined with gene-order timing, with PDX1 expression induced 1-10 days before inducing NGN3, and NGN3 expression induced 1-10 days before inducing MAFA. Additional gene induction can be included by inducing expression of a gene encoding NKX6.1 1-3 to 10 days after inducing MAFA. Delivery modalities can include viral vectors encoding the inducible expression, and the stem cell population can be unmodified adult somatic stem cells.
The invention also frames the use of reprogrammed beta cells for diabetes treatment. Reprogrammed beta cells are introduced into a patient, including delivery to the pancreas directly or via an artificial pancreas device, including surgical placement or injection of the artificial pancreas. The approach emphasizes continuous expression after induction and glucose-responsive insulin secretion while avoiding glucagon co-secretion, and includes discussion of inducible approaches for gene activation modalities.
Claims Coverage
Two independent claims are directed to inducing stem cells to differentiate into beta cells by inducible sequential expression of PDX1, NGN3, and MAFA with continuous expression after induction. A further independent therapeutic use is included as part of claim coverage in dependent form, centered on introducing reprogrammed beta cells into a patient for diabetes treatment.
Inducing sequential PDX1→NGN3→MAFA expression with continuous expression
Introducing at least one vector encoding inducible expression of PDX1, NGN3, and MAFA into unmodified adult somatic stem cells, inducing sequential expression of genes encoding PDX1 1-10 days before NGN3, and NGN3 1-10 days before MAFA, and growing until differentiated beta cells form, wherein the genes are continuously expressed after being induced.
Adult stem cell reprogramming with at least 1-day sequential gaps and continuous expression
Obtaining adult stem cells from a patient, introducing at least one vector encoding inducible expression of PDX1, NGN3 and MAFA into the adult stem cells, inducing sequential expression of genes encoding PDX1 at least 1 day before inducing NGN3 and inducing NGN3 expression at least 1 day before inducing MAFA, growing until differentiated beta cells form, wherein the genes are continuously expressed after being induced.
Across the independent claims, the central coverage is inducible sequential expression of PDX1, NGN3, and MAFA to reprogram adult stem cells into differentiated beta cells, with the additional requirement that the genes are continuously expressed after being induced. Timing constraints differ between the independent claims, and dependents refine gene timing further, add NKX6.1, narrow stem cell source, and include patient delivery for diabetes treatment.
Stated Advantages
Enables glucose-responsive insulin secretion.
Avoids glucagon co-secretion.
Continuous expression after induction.
Documented Applications
Diabetes treatment by introducing reprogrammed beta cells into a patient.
Delivery of reprogrammed beta cells for diabetes treatment to the pancreas directly or via an artificial pancreas device, including surgical placement or injection.
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