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Use of activity dependent neurotrophic factor for enhancing learning and memory: pre-and post-natal administration




Title: Use of activity dependent neurotrophic factor for enhancing learning and memory: pre-and post-natal administration.
Abstract: The present invention provides methods for improving performance (e.g., learning and/or memory) using ADNF polypeptides, by treating the subject prenatally or postnatally with an Activity Dependent Neurotrophic Factor (ADNF) polypeptide in an amount sufficient to improve postnatal learning and/or memory of the subject. ...

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USPTO Applicaton #: #20090203615
Inventors: Catherine Y. Spong, Douglas Brenneman, Iiiana Gozes


The Patent Description & Claims data below is from USPTO Patent Application 20090203615, Use of activity dependent neurotrophic factor for enhancing learning and memory: pre-and post-natal administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. National Phase application Ser. No. 10/296,849, filed Aug. 27, 2002, which is a National Phase Application under 35 U.S.C. § 371 of Application No. PCT/US2001/17758, filed May 31, 2001, which claims priority to U.S. Provisional Application No. 60/208,944 filed May 31, 2000. All of these applications are incorporated herein by reference

This application is related to U.S. Ser. No. 07/871,973 filed Apr. 22, 1992, now U.S. Pat. No. 5,767,240; U.S. Ser. No. 08/342,297, filed Oct. 17, 1994 (published as WO96/11948), now U.S. Pat. No. 6,174,862; U.S. Ser. No. 60/037,404, filed Feb. 7, 1997 (published as WO98/35042); U.S. Ser. No. 09/187,330, filed Nov. 11, 1998 (published as WO00/27875); U.S. Ser. No. 09/267,511, filed Mar. 12, 1999 (published as WO00/53217); U.S. Ser. No. 60/149,956, filed Aug. 18, 1999 (published as WO01/12654); U.S. Ser. No. 60/208,944, filed May 31, 2000; and U.S. Ser. No. 60/267,805, filed Feb. 8, 2001; herein each incorporated by reference in their entirety.

BACKGROUND

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OF THE INVENTION

Some experimental results suggest that cognitive enhancers can improve some types of learning and memory. In most cases, cognitive enhancers have been used to treat people with neurological or mental diseases, but there is a growing number of healthy, normal individuals who use these compounds in hopes of getting smarter. In addition, efficacy of these compounds in normal people is uncertain. The identification and isolation of new compounds that would improve cognitive skills would be desirable. The present invention meets this and other needs.

SUMMARY

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OF THE INVENTION

Embodiments of the invention provide methods for improving performance (e.g., learning and/or memory) by administering either prenatally or postnatally to a subject an Activity Dependent Neurotrophic Factor (ADNF) polypeptide in an amount sufficient to improve postnatal performance. The ADNF polypeptides include ADNF I and ADNF III (also referred to as ADNP) polypeptides, analogs, subsequences, and D-amino acid versions (either wholly D-amino acid peptides or mixed D- and L-amino acid peptides), and combinations thereof which contain their respective active core sites and provide neuroprotective and growth-promoting functions.

The ADNF I polypeptides have an active core site comprising the following amino acid sequence: Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (“SALLRSIPA” or in short referred to as “SAL” or “ADNF-9”; SEQ ID NO:1). The ADNF III polypeptides also have an active core site comprising a few amino acid residues, namely, the following amino acid sequence: Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (“NAPVSIPQ” or in short referred as “NAP”; SEQ ID NO:2). These ADNF polypeptides have previously been shown, each on their own, to have remarkable potency and activity in animal models related to neurodegeneration.

In one embodiment of the present invention, it is discovered that upon post-natal administration, the ADNF polypeptides also improve performance, such as learning and memory, in animal models that are afflicted with, e.g., neuropathology, Alzheimer's disease, Down's syndrome, age, or mental retardation (e.g., fragile X syndrome), as well as normal animals. The polypeptides of the invention can also be used to improve short term and reference memory.

As such, applications for the ADNF polypeptides of the present invention include improving the performance of subjects with, e.g., neuropathology; sensory-motor problems; improving the performance of subjects impaired in cognitive tasks; improving the performance of subjects with memory deficiencies; improving the performance of normal subjects; and the like. Accordingly, embodiments of the invention in suitable formulations, can be employed for decreasing the amount of time needed to learn a cognitive, motor or perceptual task. Alternatively, invention compounds, in suitable formulations, can be employed for increasing the time for which cognitive, motor or perceptual tasks are retained. As another alternative, embodiments of the invention in suitable formulations, can be employed for decreasing the quantity and/or severity of errors made in recalling a cognitive, motor or perceptual task. Such treatment may prove especially advantageous in individuals who have suffered injury to the nervous system, or who have endured disease of the nervous system. ADNF polypeptides are administered to the affected individual, and thereafter, the individual is presented with a cognitive, motor or perceptual task. Moreover, ADNF polypeptides can be administered to normal subjects to improve their performance (e.g., learning and memory). ADNF polypeptides can be particularly useful for an aged population in which capacity for memory (e.g., short term) has generally declined.

In another embodiment, the present invention is based, in part, on the discovery that when animals in utero are treated with Activity Dependent Neurotrophic Factor (ADNF) polypeptides, the ADNF polypeptides improved the animals' postnatal learning and memory, in particular, spatial learning. Surprisingly, this long term effect of ADNF polypeptides is observed even when a single dose of ADNF polypeptides is prenatally administered in the beginning of pregnancy. Quite surprisingly, this enhanced learning and memory effect of ADNF polypeptides is seen even in animals with normal mental capacity (e.g., normal mice without any mental impairment). Hence, ADNF polypeptides can push normal animals beyond their natural capacity of learning and memory and can improve their cognitive skills.

As described above, these ADNF polypeptides have previously been shown to have remarkable potency and activity in animal models, particularly in those related to neurodegeneration. However, the effects of ADNF polypeptides were observed when they were postnatally administered to the animals. It has now been discovered for the first time that the prenatal treatment with ADNF polypeptides can enhance the animals' postnatal learning and memory, both for normal animals as well as for mentally impaired animals.

The present discovery has significant applications in human subjects in improving their learning, memory, and associated mental processes. Even normal human subjects can benefit from the prenatal treatment with ADNF polypeptides. Moreover, the present discovery has applications in subjects who are mentally compromised. For example, if a fetus is diagnosed as having mental retardation or Down's syndrome, the fetus in utero can be treated with ADNF polypeptides so that its postnatal learning and memory skills can be ameliorated. Even without a specific diagnosis of mental retardation or Down's syndrome, ADNF polypeptides can be prophylactically administered to the fetus in certain circumstances. For example, if there is a family history of mental retardation (e.g., fragile X syndrome), ADNF polypeptides can be prophylactically administered to the fetus in utero. In another example, if the mother is older (e.g., 35 years or older) and thus, has a higher risk of having a baby with Down's syndrome or other genetic defects, ADNF polypeptides can be prophylactically administered to the fetus in utero.

Various parameters can be measured to determine if an ADNF polypeptide or a combination of ADNF polypeptides improves performance (e.g., learning and memory) in vivo. For example, the hidden platform test of the Morris water maize can be used described in the materials and methods section below can be used. Generally, mice that are treated with ADNF polypeptides and control mice (that are not treated with ADNF polypeptides) are trained to escape swimming task by learning the position of a hidden platform and climbing on it. The time it takes them to complete this task is defined as the escape latency. This test can be conducted one or more times daily for a number of days. One parameter that is indicate of improved learning and memory is the reduction in latency in escaping swimming task by climbing onto a hidden platform. See, also, methods described in Gozes et al., Proc. Natl. Acad. Sci. USA 93:427-432 (1996), incorporated herein by reference. Animals treated with suitable ADNF polypeptides would show improvement in their learning and memory capacities compared to the control that are not treated with ADNF Polypeptides. Embodiments of the invention are not limited by examples of test used to measure performance. Any suitable test methods can be used to measure performance, such as learning and memory.

Other methods known in the art can be used in human subjects to determine if an ADNF polypeptide or a combination of ADNF polypeptides improves performance (e.g., learning and memory) in vivo. For example, these methods include assessment of memory or learning over time by the Randt Memory Test (Randt et al., Clin. Neuropsychol. 2:184 (1980), Wechsler Memory Scale (J. Psych. 19:87-95 (1945), Forward Digit Span test (Craik, Age Differences in Human Memory, in: Handbook of the Psychology of Aging, Birren and Schaie (Eds.), New York, Van Nostrand (1977), Mini-Mental State Exam (Folstein et al., J. of Psych. Res. 12:189-192 (1975), or California Verbal Learning Test (CVLT)). See, also, U.S. Pat. No. 6,030,968. In these tests, factors unrelated to effects of ADNF polypeptides (e.g., anxiety, fatigue, anger, depression, confusion, or vigor) are controlled for. See, U.S. Pat. No. 5,063,206. Methods for assessing and controlling for subjective factors is known in the art and determined by such standard clinical tests such as the BECK Depression Scale, Spielberger Trait State Anxiety test, and POMS test (Profile of Mood State).

In one aspect, the present invention provides a method for improving performance (e.g., learning and/or memory), the method comprising administering either postnatally or prenatally to a subject an Activity Dependent Neurotrophic Factor (ADNF) polypeptide in an amount sufficient to improve postnatal performance (e.g., learning and/or memory). Methods of the invention can be applied to any subjects, e.g., subjects who are afflicted with neuropathology, such Alzheimer's disease, Down's syndrome, etc. or normal subjects, either young or old, or subjects in utero. In one embodiment, the ADNF polypeptide is prenatally administered to the subject who has normal mental capacity. In another embodiment, the subject has mental retardation (e.g., fragile x syndrome), a family history of mental retardation, Down's syndrome, or a mother who is at least 35 years of age when pregnant with the subject. Preferably, if the subject has mental retardation, it is not caused by excessive maternal alcohol consumption during pregnancy (i.e., mental retardation is not part of fetal alcohol syndrome).

In one embodiment, the ADNF polypeptide is administered prenatally, e.g., to a pregnant mother, e.g., by intraperitoneal administration or oral administration.

In another embodiment, the ADNF polypeptide is administered postnatally, e.g., by intraperitoneal administration or oral administration. In one embodiment, the ADNF polypeptide is administered at the time of neural tube development and/or closure of the neural tube.

In one embodiment, the method comprises administering an ADNF polypeptide, wherein the ADNF polypeptide is an ADNF I polypeptide comprising an active core site having the amino acid sequence of Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1)). In another embodiment, the method comprises administering a full length ADNF I polypeptide. In yet another embodiment, the method comprises administering an ADNF I polypeptide which consists of the amino acid sequence of Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1). In yet another embodiment, the method comprises administering an ADNF I polypeptide, wherein the ADNF I polypeptide is selected from the group consisting of: Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:14); Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:15); Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:16); Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:17); Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:18); and Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:19). In yet another embodiment, the method comprises administering an ADNF I polypeptide having up to about 20 amino acids at least one of the N-terminus or the C-terminus of the active core site. In certain embodiments, the ADNF I polypeptide has up to 20 amino acids at both the N-terminus and the C-terminus of the ADNF I polypeptide.

In another embodiment, the method comprises administering an ADNF polypeptide, wherein the ADNF polypeptide is an ADNF III polypeptide comprising an active core site having the amino acid sequence of Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2). In yet another embodiment, the method comprises administering a full length ADNF III polypeptide. In yet another embodiment, the method comprises administering an ADNF I polypeptide which consists of the amino acid sequence of Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2). In yet another embodiment, the method comprises administering an ADNF III polypeptide, wherein the ADNF III polypeptide is selected from the group consisting of: Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:20); Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-Ser (SEQ ID NO:21); Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-Ser (SEQ ID NO:22); and Ser-Val-Arg-Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-Ser (SEQ ID NO:23). In yet another embodiment, the method comprises administering an ADNF III polypeptide having up to about 20 amino acids at least one of the N-terminus and the C-terminus of the active core site. In certain embodiments, the ADNF III polypeptide has up to 20 amino acids at both the N-terminus and the C-terminus of the ADNF III polypeptide.

In yet another embodiment, the method comprises administering a mixture of an ADNF I polypeptide and an ADNF III polypeptide. Any one or more of the ADNF I polypeptides described herein can be mixed with any one or more of the ADNF III polypeptides described herein in this and other aspects of the invention.

In another embodiment, the active core site of the ADNF polypeptide comprises at least one D-amino acid. In another embodiment, the active core site of the ADNF polypeptide comprises all D-amino acids.

In yet another embodiment, at least one of the ADNF polypeptide is encoded by a nucleic acid which is administered to the subject.

In yet another embodiment, the ADNF polypeptide improves a short term memory. In yet another embodiment, the ADNF polypeptide improves a reference memory. In yet another embodiment, the ADNF polypeptide is administered intranasally or orally.

These and other aspects of the present invention will become apparent to those skilled in the art from the following detailed description of the invention, the accompanying drawings, and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

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FIG. 1 AF64A-treated rats exhibit an impairment in learning and memory that is ameliorated by intranasal administration of ADNF-9. Two daily water maze tests (A and B, respectively) were performed on adult rats. Groups tested were: 1. control animals treated with vehicle (20 animals, open circles); 2. AF64A-treated animals intranasally administered with vehicle (27 animals, open squares); 3. control animals treated by intranasal administration of ADNF-9 (closed circles, 12 animals); 4. AF64A-treated animals intranasally administered with ADNF-9 (19 animals, closed squares). (A) Latency measured in seconds (mean±standard error of the mean) to reach the hidden platform in its new daily location (indicative of intact reference memory, Gordon et al., Neurosci. Lett. 199:1-4 (1995)) is depicted. Tests were performed over four consecutive days. (B) Latency measured in seconds to reach the hidden platform 0.5 min. after being on it (indicative of intact working memory processes, Gordon et al., Neurosci. Lett. 199:1-4 (1995); Gozes et al., J. Neurobiol. 33:329-342. (1997a)) tested over four consecutive days. There were no differences between animals treated with vehicle and untreated animals (data not shown). (C) On day 5 of testing, the platform was removed and a spatial probe test was performed. The animals were allowed to swim for 120 sec. and the time spent by the animal at the platform quadrant was recorded.

FIG. 2 AF64A-treated rats exhibit impairments in learning and memory that are ameliorated by intranasal administration of NAP. The same experiment reported in FIG. 1 (A, B, C, respectively) was repeated, except that the peptide used was NAP and the number of animals per each of the experimental groups was 10-20 and 27 for the AF64A-treated group.

FIG. 3 Intranasally applied [3H]-NAP reaches the body and the brain. (A) Animals were sacrificed at indicated times after administration and tissue samples were weighed and assayed (in duplicates) for radioactivity in a β-counter, a mean of four animals is depicted. (B) Brains were dissected at indicated time points and radioactivity monitored. (C, D) Intact [3H]-NAP reached the brain after intranasal administration. Radioactive tissue samples (cerebral cortex) were homogenized and subjected to low-speed centrifugation. Supernatants (30 minutes following application, closed circles, C, and 60 minutes following application, closed triangles, D) were analyzed by HPLC fractionation against [3H]-NAP stock (open circles). Samples were monitored for radioactivity (dpm) in a β-counter. All results were calculated to depict radioactivity as fmoles of NAP/g tissue. (E) The experiment was repeated with three additional animals, here the animals were 200 g each instead of 250-300 g in A-D and small visible blood vessels were removed utilizing watchmaker\'s forceps (no. 5).

FIG. 4 (A) Intranasal application of NAP prevents reduction in choline acetyl transferase activity in AF64A-treated rats. Incorporation of radiolabeled choline into acetyl choline is shown. Results were calibrated against control (100%). Experiments utilizing three animals per group (each in triplicates) were conducted and analyzed as described in the text. (B) AF64A-treated rats exhibit impairments in learning and memory, long-lasting effects of NAP, but not of ADNF-9 treatment. Ten male rats (as described in the methods section) were used per experimental group. Four groups were used, three were treated with AF64A and one group was treated with saline (control). The rats were allowed a week for recovery, and then two AF64A groups were treated (intranasally) with either ADNF-9 or NAP. Following 5 treatment days the animals were allowed to recover for two days and then subjected to daily water-maze tests (as in FIGS. 1 and 2). The difference between this experiment and the experiments in FIGS. 1 and 2 is that the animals did not receive a daily intranasal application of peptides prior to the behavioral test. The figure depicts the second daily test indicative of short-term memory.

FIG. 5 illustrates the effects of prenatal treatment of animals with a mixture of L-NAP and L-SAL (intraperitoneal injection) on learning as assessed by a Morris water maze test.

FIG. 6 illustrates the effects of prenatal treatment of animals with a mixture of D-NAP and D-SAL (oral administration) on learning as assessed by a Morris water maze test.

FIG. 7 illustrates the effects of prenatal treatment of animals with D-SAL (oral administration) on learning as assessed by a Morris water maze test.




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stats Patent Info
Application #
US 20090203615 A1
Publish Date
08/13/2009
Document #
File Date
12/31/1969
USPTO Class
Other USPTO Classes
International Class
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Prenatal

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Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai   Cyclopeptides   16 To 24 Peptide Repeating Units In Known Peptide Chain  

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20090813|20090203615|use of activity dependent neurotrophic factor for enhancing learning and memory: pre-and post-natal administration|The present invention provides methods for improving performance (e.g., learning and/or memory) using ADNF polypeptides, by treating the subject prenatally or postnatally with an Activity Dependent Neurotrophic Factor (ADNF) polypeptide in an amount sufficient to improve postnatal learning and/or memory of the subject. |Ramot-At-Tel-aviv-University-Ltd