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Patent Issued for Materials and Methods for Gene Mediated Therapy of Psychiatric Disorders

February 20, 2014



By a News Reporter-Staff News Editor at Gene Therapy Weekly -- A patent by the inventors Kaplitt, Michael (New York, NY); Alexander, Brian L. (New York, NY), filed on October 31, 2008, was published online on February 4, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Cornell University).

Patent number 8642341 is assigned to Cornell University (Ithaca, NY).

The following quote was obtained by the news editors from the background information supplied by the inventors: "The pathophysiology of psychiatric disorders and, in particular, the cellular and molecular mechanisms responsible for the maintenance of severe forms of psychiatric disorders such as depression and other mood disorders remains poorly understood. This is so despite evidence indicating that common pathways are involved in multiple psychological disorders. For example, compounds that target or affect the serotonin and/or norepinephrine receptor systems have been used to treat a variety of psychiatric disorders including, for example, depression, affective disorders, psychoses, and addiction. Nonetheless, little progress has been made to identify genes and gene products that may be suitable for use in gene therapy of psychiatric disorders.

"The p11 gene product, also known as s100A10, is a member of the s100 protein family that exists as a heterotetramer in which a central p11 dimer anchors two annexin A2 chains (Lewit-Bentley et al., Cell. Biol. Int., 24: 799-802 (2000)). Northern blot analyses show that p11 expression, while ubiquitous, is low in liver, heart, and testes, moderate in brain, spleen, and thymus, and high in kidney, intestine, and lung (Saris et al., J. Biol. Chem., 262: 10663-10671 (1987)). Although p11 shares significant sequence homology with other members of the S100 family, several amino acid substitutions and deletions render it unique (Gerke et al., EMBO J., 4: 2917-2920 (1985); Glenney, J. Biol. Chem., 261: 7247-7252 (1986)). Like other S100 family proteins, p11 possesses two EF-hand loops, although differences in amino acid sequence apparently compromise the ability of p11's EF loops to bind calcium, resulting in a permanently activated state (Rety et al., Nat. Struct. Biol., 6: 89-95 (1999)). Cryo-electron microscopy studies show that the p11-annexinA2 heterotetramer fosters vesicle aggregation at the plasma membrane by forming symmetric junctions between opposing membrane surfaces (Lambert et al., J. Mol. Biol., 272: 42-55 (1997)). In this way, the p11-annexinA2 complex may also stabilize membrane proteins in a particular configuration.

"Studies have identified interactions between p11 and membrane-resident proteins of neuronal cells, including serotonin receptor. The relationship of p11 and trafficking protein for membrane-bound proteins was first identified in yeast two-hybrid studies. In particular, the tetrodotoxin-resistant sodium channel, Nav 1.8, and the potassium channel, TWIK-related acid-sensitive K (TASK) 1, were identified as binding partners for p11, and their translocation to the plasma membrane was reliant upon the presence of a p11-annexinII complex (Girard et al., EMBO J., 21: 4439-4448 (2002); Okuse et al., Nature, 417: 653-656 (2002)). Further studies indicated that surface expression of these proteins were affected by levels of p11 (Poon et al., FEBS Lett., 558: 114-118 (2004)). The trafficking of three other membrane-resident proteins also has been linked to p11 expression, namely the epithelial Ca.sup.2+ channels TRPV5 and TRPV6, the acid-sensing ion channel ASIC1a, and the serotonin 1B receptor (Donier et al., J. Biol. Chem., 280: 38666-38672 (2005); Svenningsson et al., Science, 311: 77-80 (2006); van de Graaf et al., EMBO J., 22: 1478-1487 (2003)).

"A recent report indicated that p11 overexpression increases surface expression of 5-HT1B, while p11 knockout mice demonstrate fewer binding sites for 5-HT1B receptor antagonists (Svenningsson et al., Science, 311: 77-80 (2006)). The report was not able to establish the role of p11 in depression-like states because of a number of confounding factors, some of which are associated with the study's use of transgenic mice. For example, the study could not distinguish between the developmental and physiological role of mice with a transgenically disrupted p11 gene. In another example, the study found that p11 overexpression in transgenic mice produced a generalized hyperactivity (Id. at 79).

"Accordingly, there is a need for gene products that are useful in the treatment and understanding of psychiatric disorders, such as depression."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The invention provides materials and methods useful in the treatment and understanding of psychiatric disorders. In one aspect, the invention provides a viral vector comprising a p11 nucleic acid. The viral vector can be, for example, a retrovirus vector, a lentivirus vector, an adenovirus vector, or an adeno-associated virus vector, and the p11 nucleic acid can be, for example, a p11 cDNA.

"The viral vector of the invention can be used in a method of increasing p11 in a mammal. Generally, the method includes delivering a viral vector of the invention to the mammal, so as to cause expression of the p11 nucleic acid, thereby increasing p11 in the mammal. The method can include delivering the viral vector to a portion of the mammal's brain, e.g., the nucleus accumbens, thereby increasing the level of p11 in the portion of the brain of the mammal relative to the basal level of p11 in that portion of the brain.

"The invention also provides a method of treating a psychiatric disorder in a mammal. The method generally includes delivering a therapeutic gene to the nucleus accumbens of a mammal suffering from a psychiatric disorder, thereby treating the psychiatric disorder. The therapeutic gene can be a p11 nucleic acid, which can be delivered in a viral vector of the invention to the nucleus accumbens.

"The invention further provides a method for improving the responsiveness of a mammal to treatment for a psychiatric disorder. The method includes delivering a viral vector of the invention to the nucleus accumbens of a mammal suffering from a psychiatric disorder. The method further includes subjecting the mammal to a treatment for the psychiatric disorder, which is a treatment other than with gene therapy, whereby the mammal's responsiveness to treatment for the psychiatric disorder is improved.

"Additionally, the invention provides a method of improving the responsiveness of a mammal to treatment for depression. The method includes delivering a viral vector of the invention to the nucleus accumbens of a mammal suffering from depression (e.g., major depressive disorder or refractory depression), and then subjecting the mammal to a treatment for depression other than with gene therapy, so as to improve the mammal's responsiveness to treatment for the psychiatric disorder.

"Furthermore, the invention provides a method for treating one or more symptoms of depression in a mammal. The method includes delivering a therapeutic gene to the nucleus accumbens of a mammal exhibiting one or more symptoms of depression to thereby treat the one or more symptoms of depression. The method can be used to treat a mammal suffering from major depressive disorder or from refractory depression. The therapeutic gene can be a p11 nucleic acid, which can be delivered in a viral vector of the invention to the nucleus accumbens.

"In another aspect, the invention provides an animal model for depression therapy, which can be produced by selectively delivering p11 nucleic acid to the nucleus accumbens of a non-human mammal.

"In yet another aspect, the invention provides an animal model of depression produced by locally reducing a gene product, e.g., p11, in an isolated region of a brain, e.g., the nucleus accumbens, of a non-human mammal without reducing the gene product throughout the brain of the mammal."

URL and more information on this patent, see: Kaplitt, Michael; Alexander, Brian L.. Materials and Methods for Gene Mediated Therapy of Psychiatric Disorders. U.S. Patent Number 8642341, filed October 31, 2008, and published online on February 4, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=86&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=4265&f=G&l=50&co1=AND&d=PTXT&s1=20140204.PD.&OS=ISD/20140204&RS=ISD/20140204

Keywords for this news article include: Biotechnology, Viral, Virus, Peptides, Proteins, Autacoids, Serotonin, Treatment, Amino Acids, Tryptamines, Gene Therapy, Therapeutics, Bioengineering, Biogenic Amines, Organic Chemicals.

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Source: Gene Therapy Weekly


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