NEURAL STEM CELL THERAPY FOR OBESITY AND DIABETES
Methods are provided of treating obesity or an obesity comorbidity in a mammalian subject comprising administering to the subject an amount of an agent effective to treat obesity or the obesity comorbidity, which agent inhibits (i) IκB kinase β (IKKβ) activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or (ii) Notch signaling in a manner so as to permit the agent to enter the hypothalamus of the subject. Assays are also provided for identifying candidate agents for treating obesity.
1 . A method of treating obesity or an obesity comorbidity in a mammalian subject comprising administering to the subject an amount of an agent effective to treat obesity or the obesity comorbidity, which agent inhibits (i) IκB kinase β (IKKβ) activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or (ii) Notch signaling, in a manner so as to permit the agent to enter the hypothalamus of the subject.
2 . The method of claim 1 , wherein the agent is an inducible pluripotent cell comprising a heterologous nucleic acid or having a genetic sequence deleted therein or a neural stem cell comprising a heterologous nucleic acid or having a genetic sequence deleted therein.
3 . The method of claim 2 , wherein the inducible pluripotent cell or the neural stem cell is a human or a human-derived cell.
4 . The method of claim 2 , wherein the neural stem cell is a hypothalamic stem cell.
5 . The method of claim 2 , wherein the inducible pluripotent cell or neural stem cell comprises a heterologous nucleic acid encoding a dominant-negative IκBα.
6 . The method of claim 2 , wherein the inducible pluripotent cell or neural stem cell comprises a heterologous nucleic acid encoding dominant-negative IκBα transfected via means of a viral vector.
7 . The method of claim 6 , wherein viral vector is lentiviral.
8 . The method of claim 2 , wherein the inducible pluripotent cell or neural stem cell has a IKKβ genetic sequence deleted.
9 . The method of claim 2 , wherein the inducible pluripotent cell or neural stem cell comprises a heterologous nucleic acid comprising a shRNA directed against a Notch 1, Notch 2, Notch 3 or Notch 4.
10 . The method of claim 9 , wherein the inducible pluripotent cell or neural stem cell comprises a shRNA directed against a Notch 1, Notch 2, Notch 3 or Notch 4 transfected via means of a viral vector.
11 . The method of claim 10 , wherein viral vector is lentiviral.
12 . The method of claim 1 , wherein the agent is administered centrally.
13 . The method of claim 1 , wherein the obesity comorbidity is treated and the comorbidity is type 2 diabetes.
14 . A method of identifying an agent as a candidate treatment for obesity or an obesity comorbidity in a subject, the method comprising testing if the agent inhibits IKKβ/NF-κB activation by contacting the IKKβ and/or NF-κB with the agent, and determining if the agent is an inhibitor of IKKβ/NF-κB activation,
wherein if the agent does not inhibit IKKβ/NF-κB activation it is not a candidate treatment, and wherein if the agent does inhibit IKKβ/NF-κB activation it is a candidate treatment or a method of identifying an agent as a candidate treatment for obesity or an obesity comorbidity in a subject, the method comprising testing whether the agent inhibits IKKβ/NF-κB in the hypothalamus of a non-human mammal, and determining if the agent is an inhibitor of IKKβ/NF-κB activation in the hypothalamus,
wherein if the agent inhibits IKKβ/NF-κB in the hypothalamus of the non-human mammal it is a candidate treatment, and wherein if the agent does not inhibit IKKβ/NF-κB in the hypothalamus of the non-human mammal it is not a candidate treatment or a method of identifying an agent as a candidate treatment for obesity or an obesity comorbidity in a subject, the method comprising testing if the agent inhibits a Notch 1, Notch 2, Notch 3 or Notch 4 in the hypothalamus of a non-human mammal, and determining if the agent is an inhibitor of a Notch 1, Notch 2, Notch 3 or Notch 4 in the hypothalamus,
wherein if the agent inhibits Notch 1, Notch 2, Notch 3 or Notch 4 in the hypothalamus of the non-human mammal it is a candidate treatment, and wherein if the agent does not inhibit Notch 1, Notch 2, Notch 3 or Notch 4 in the hypothalamus of the non-human mammal it is not a candidate treatment.
15 - 16 . (canceled)
17 . The method of claim 1 , wherein the agent is a small organic molecule of 1200 daltons or less, an RNAi molecule, a peptide or an antibody or antibody-fragment.
18 . A pharmaceutical composition for treating obesity or an obesity comorbidity, comprising an inducible pluripotent cell comprising a heterologous nucleic acid or having a genetic sequence deleted therein or a neural stem cell comprising a heterologous nucleic acid or having a genetic sequence deleted therein and a pharmaceutically acceptable carrier, wherein the inducible pluripotent cell or neural stem cell comprises a heterologous nucleic acid encoding a dominant-negative IκBα or comprises a dominant-negative IκBα transfected via means of a viral vector, or has a IKKβ genetic sequence deleted, or comprises a shRNA directed against a Notch 1, Notch 2, Notch 3 or Notch 4.
19 . (canceled)