Method of enhancing neural stem cell proliferation, differentiation, and survival using pituitary adenylate cyclase activating polypeptide (PACAP)

Patent Number: 7,368,115

Pharmaceutical activation of stem cells is arguably the next major revolution in medicine. The current patent is assigned to a Canadian stem cell company, Stem Cell Therapeutics (TSX-V:SSS), which already has entered Phase II clinical trials with pharmaceutical activators of endogenous stem cells for the treatment of stroke. While the ongoing clinical work of Stem Cell Therapeutics involves administration of erythropoietin and human chorionic gonadotrophin for activation of endogenous neural stem cells, the current patent covers the use of a peptide hormone for a similar purpose.

The hormone covered is pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotransmitter involved in control of metabolism, neurological function, and development. PACAP belongs to a superfamily of nine structurally related hormones that also share anatomical distribution (brain and gut), function (activation of cAMP), and receptors (seven-transmembrane receptor). The hormones belonging to this superfamily include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM), PACAP, secretin, and vasoactive intestinal polypeptide (VIP). The reason we mention these similarities is because GLP receptor activators have previously been shown to induce activation of endogenous pancreatic stem cells.

A brief understanding of the current patent can be seen by reading the first issued claim "A method for increasing neural stem cell and/or neural stem cell progeny number comprising: adding pituitary adenylate cyclase-activating polypeptide (PACAP) to multipotent neural stem cells in an amount effective to increase neural stem cell and/or neural stem cell progeny number, said method further comprising adding prolactin." This issued claim is very potent, it is not restricted to in vitro or in vivo.

The dependent claims cover not only stimulation of proliferation but also inhibition of neural stem cell apoptosis. Stem cell activation/protection includes both exogenous stem cells, as well as endogenous stem cells, such as those from the subventricular zone. The use of PACAP together with prolactin is also covered for treatment of neurodegenerative diseases, stroke, Parkinson's, Alzheimer's, and Huntington's. Combinations of PACAP with other agents such as FGF-2, heparan sulphates, and EGF are also covered.

In the examples section of the specification, in vitro stimulation of neurospheres, as well as in vivo induction of subventricular zone neurons is provided. Interestingly, an independent group (Wang et al. Neuroprotective effects of PACAP27 in mice model of Parkinson's disease involved in the modulation of K(ATP) subunits and D2 receptors in the striatum. Neuropeptides. 2008 Apr 25) has published that administration of PACAP has a therapeutic effect on an animal model of Parkinson's.

View this patent on the USPTO website.