| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 2, 2002 |
| PATENT TITLE |
Learning and short term memory defects with Neurofibromatosis 1 (NF1) expression |
| PATENT ABSTRACT | The present invention provides methods for treating learning and short term memory defects associated with a defect in the NF1 protein. The present invention also provides methods for screening a pharmaceutical agent for its ability to treat learning and short term memory defects associated with a defect in the NF1 protein |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 23, 2000 |
| PATENT REFERENCES CITED |
Banfi et al. Journal of Pharmacological Methods 8:255-263 1982.* Banfi et al. J. Pharmacological Methods 8(4):255-263 Dec. 1982; Abstract from Dialog, Medline Database.* Silva, A.J. et al., "A Mouse Model For The Learning And Memory Deficits Associated With Neurofibromatosis Type I, " Nature Genetics, 15:281-284 (Mar. 15, 1997). Silva, A.J. et al., "Un Modele De Souris Pour Etudier Les Deficits De L'Apprentissage Et De La Memoire Associes A La Neurofibromatose De Type I," Pathologie Biologie, 46 (9) :697-698 (Nov. 1998). Silva, A.J., Elgersma, Y. and Costa R.M., "Molecular And Cellular Mechanisms Of Cognitive Function: Implications For Psychiatric Disorders," Biol. Psychiatry, 47 (3) :200-209 (Feb. 2000). Gutmann, D.H., "Recent Insights Into Neurofibromatosis Type I," Arch. Neurol., 55:778-780 (Jun. 1998). The, I. et al., "Rescue Of A Drosophila NF1 Mutant Phenotype By Protein Kinase A," Science, 276:791-794 (May 1997). Guo, H.F. et al., "Requirement Of Drosophila NF1 For Activation Of Adenylyl Cyclase By PACAP38-Like Neuropeptides," Science, 276:795-798 (May 1997). |
| PATENT GOVERNMENT INTERESTS | This invention was made with Government support, in whole or in part, under Grant Nos. NIH 5R01 NS34779-04 and NIH 5P01 HD33098-03 awarded by the National Institutes of Health. The United States government has certain rights in this invention |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for screening a pharmaceutical agent for its ability to treat a short term memory defect in an animal, wherein the short term memory defect is associated with a defect in the Neurofibromatosis 1 protein, comprising: a) administering said pharmaceutical agent to an animal with a short term memory defect associated with a defect in the Neurofibromatosis 1 protein; b) training said animal treated in step a) under conditions appropriate to produce short term memory formation in said animal; c) assessing short term memory formation in said animal trained in step b); and d) comparing short term memory formation assessed in step c) with short term memory formation produced by the training protocol of step b) in a control animal to which said pharmaceutical agent has not been administered, wherein the pharmaceutical agent is identified as one having the ability to treat said short term memory defect in said animal if short term memory formation assessed in step c) is greater than short term memory formation produced in said control animal. 2. The method of claim 1 wherein said animal is a mammal. 3. The method of claim 1 wherein said animal is a Drosophila species. 4. The method of claim 2 wherein said animal is a rodent. 5. A method for screening a pharmaceutical agent for its ability to treat a learning defect in an animal, wherein the defect is associated with a defect in the Neurofibromatosis 1 protein, comprising: a) administering said pharmaceutical agent to an animal with a learning defect associated with a defect in the Neurofibromatosis 1 protein; and b) training said animal treated in step a) under conditions appropriate for learning by said animal; c) assessing learning ability by said animal trained in step b); and d) comparing learning ability assessed in step c) with learning ability assessed using the training protocol of step b) by a control animal to which said pharmaceutical agent has not been administered, wherein the pharmaceutical agent is identified as one having the ability to treat said learning defect in said animal if learning ability assessed in step c) is greater than learning ability by said control animal. 6. The method of claim 5 wherein said animal is a manmmal. 7. The method of claim 5 wherein said animal is a rodent. 8. The method of claim 5 wherein said animal is a Drosophila species. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION Learning, which is the modification of behavior in response to experiences, is one of the most characteristic attributes of animals, including humans. An important feature of learning is that it is adaptive. The animal, having learned, responds in ways that improve its survival and reproductive success. Different animals, even of the same species, learn things if they are exposed to different environments. Another attribute that many animals, including humans, possess is memory of what was once experienced or learned. This attribute has been studied for many decades with much information now available that explains many of its ramifications. For example, memory can be classified as short term memory lasting seconds to minutes or as long term memory lasting days to weeks to years. Short term memory refers to the ability to recall an experience or what was learned for a short period of time. Long term memory refers to the ability to remember an experience or what was learned long after the experience has occurred or long after that which was learned. A newly acquired experience initially is susceptible to various forms of disruption. With time, however, the new experience becomes resistant to disruption (McGaugh and Herz, Memory Consolidation, Albion, San Francisco, 1972; Tully, T. et al., Cold Spring Harbor Symp. Quant. Biol., 55:203-211 (1990)). This observation has been interpreted to indicate that a labile, short-term memory is "consolidated" into a more stable, long-term memory. Learning and/or memory defects impair the ability of an animal to learn and/or remember an experience, which can be detrimental to the survival and reproductive success of the animal. Accordingly, there is considerable interest in developing techniques for treating learning and/or memory defects. SUMMARY OF THE INVENTION The present invention relates to methods of treating a learning or short term memory defect associated with a defect in the Neurofibromatosis 1 (NF1) protein in an animal (particularly a human or other mammal or vertebrate) in need thereof. The NF1 protein defect is either a diminution in the amount of NF1 protein produced, a diminution in the activity or action of the NF1 protein produced or both a diminution in amount and activity or action of NF1 protein. In one embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein a NF1 compound such as exogenous NF1, NF1 analog, NF1-like moleculeogically active NF1 fragment or NF1 fusion protein. In a second embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein a nucleic acid sequence encoding exogenous NF1, NF1 analog, NF1-like molecule, biologically active NF1 fragment or NF1 fusion protein. In a third embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein an effective amount of a pharmaceutical agent that stimulates cyclic AMP formation in the same manner as NF1. In a fourth embodiment, the method comprises administering to an animal with a learning or short term memory defect associated with a defect in the NF1 protein a pharmaceutical agent that activates protein kinase A (PKA) activity in the same manner as NF1. The present invention also relates to methods for screening a pharmaceutical agent for its ability to treat a short term memory defect associated with a defect in the NF1 protein in an animal (particularly a human or other mammal or vertebrate) in need thereof. The method comprises (a) administering a pharmaceutical agent to an animal with a short term memory defect associated with a defect in the NF1 protein; (b) training the animal under conditions appropriate to produce short term memory formation in the animal; (c) assessing short term memory formation in the animal trained in step (b); and (d) comparing short term memory formation assessed in step (c) with short term memory formation produced in the control animal to which said pharmaceutical agent has not been administered. If the short term memory formation assessed in the animal treated with the pharmaceutical agent is greater than the short term memory formation assessed in the control animal, the pharmaceutical agent is identified as one having the ability to treat a short term memory defect associated with a defect in the NF1 protein. The invention further relates to methods for screening a pharmaceutical agent for its ability to treat a learning defect associated with a defect in the NF1 protein in an animal (particularly a human or other mammal or vertebrate) in need thereof The method comprises (a) administering a pharmaceutical agent to an animal with a learning defect associated with a defect in the NF1 protein; (b) training the animal under conditions appropriate for learning by the animal; (c) assessing learning ability in the animal trained in step (b); and (d) comparing learning ability assessed (c) with learning ability in the control animal to which said pharmaceutical agent has not been administered. If the learning ability assessed in the treated with the pharmaceutical agent is greater than the learning ability assessed in the control animal, the pharmaceutical agent is identified as one having the ability to treat a learning defect associated with a defect in the NF1 protein. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a graphical representation of the Drosophila NF1 gene. FIG. 1B is a diagram representation of the percentage amino acid identity between Drosophila and human NF1 segments. FIGS. 2A-2D is a pictorial representation of the amino acid alignment of the Drosophila NF1 protein (SEQ ID NO:1) and human NF1 protein (SEQ ID NO:2). FIG. 3A is a bar graph representation of results showing the NF1 learning defects observed in both the original and outcrossed isogenic (marked by u in superscript) genetic background. K33=control flies (parental line for NF1 mutant flies; wildtype); NF1.sup.P1 =NF1 mutant flies; NF1.sup.P2 =NF1 mutant flies; K33.sup.u =control flies K33 flies outcrossed with isogenic line w.sup.118); NF1.sup.P1u =NF1 mutant flies (NF1.sup.P1 outcrossed with isogenic line w.sup.1118); NF1.sup.P2u =NF1 mutant flies (NFP1.sup.P2 outcrossed with isogenic line w.sup.1118). The number of assays for each group is indicated above each error bar. FIG. 3B is a bar graph representation of results showing the effect of heat shock induction on learning scores in K33.sup.u, NF1.sup.P2 and hsNF1/+; K33 flies. K33.sup.u =control flies; NF1.sup.P2 =NF1 mutant flies; hsNF1/+; K33=heterozygous transgenic NF1 flies; hs=heat shock. The number of assays for each group is indicated above each error bar. FIG. 3C is a bar graph representation of results showing rescue of the NF1 learning defect by induced expression of the NF1 transgene. K33=control flies; NF1.sup.P2 =NF1 mutant flies; hsNF1/+; NF1.sup.P2 =heterozygous transgenic NF1 flies; hs=heat shock. The number of assays for each group is indicated above each error bar. FIG. 4A is a bar graph representation of results comparing the learning scores of NF1.sup.P2 and rut.sup.1 single-mutant flies and rut.sup.1 ; NF1.sup.P2 double-mutant flies. K3=control flies; NF1.sup.P2 =NF1 mutant flies; rut.sup.1 =rutabaga mutant flies; rut.sup.1 ; NF1.sup.P2 =rutabaga and NF1 double mutant flies. FIG. 4B is a bar graph representation of results showing rescue of NF1 learning defects by induced expression of a constitutively active catalytic subunit of cAMP-dependent protein kinase (PKA*). NF1.sup.P1 and NF1.sup.P2 =NF1 mutant flies; hsPKA; NF1.sup.P1 and hsPKA; NF1.sup.P2 =NF1 mutant flies carrying a transgene encoding the PKA* subunit; K33=control flies; hsPKA/+; K33=K33 flies carrying a transgene encoding the PKA* subunit; hs=heat shock. From left to right, n=6, 6, 6, 5, 4, 6, 6, 6, 4, 4. FIG. 4C is a graphic representation of results showing rescue of short-term memory defect by induced expression of the PKA* subunit. K33=control flies; NF1.sup.P2 =NF1 mutant flies; hsPKA; NF1.sup.P2 =NF1 mutant flies carrying a transgene encoding the PKA* subunit; hs=heat shock. n=6-12. FIGS. 5A and 5B are bar graph representations showing the results of biochemical assays of the effect of NF1 on GTP.gamma.S-stimulated adenylyl cyclase activity in brain tissues. WT=wildtype (K33); NF1.sup.P1 and NF1.sup.P2 =NF1 mutants; hsNF1; NF1.sup.P2 =heterozygous transgenic NF1 flies; rutabaga=rutabaga mutant; rutabaga; NF1.sup.P2 =rutabaga and NF1 double mutant flies. For FIG. 5A, each data point (mean.+-.SEM) is the average of 4 independent experiments. For FIG. 5B, data points are the average of 3 independent experiments. FIGS. 5C and 5D are graphic representations showing the results of biochemical assays of the effect of NF1 on Ca.sup.2+ -dependence of adenylyl cyclase activity in abdominal tissues. WT=wildtype (K33); NF1.sup.P2 =NF1 mutant; rutabaga=rutabaga mutant; rutabaga; NF1.sup.P2 =rutabaga and NF1 double mutant flies; +GTP.gamma.S=GTP.gamma.S-stimulated adenylyl cyclase activity. For FIG. 5C, the average of 8 independent experiments is shown. For FIG. 5D, the average of 6 independent experiments is shown |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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