University of California

Neotope Biosciences Limited

Janssen Alzheimer Immunotherapy

Neuropore Therapies, Inc.

Prothena Biosciences Limited

Eliezer Masliah

Edward Rockenstein

Dale Bernard Schenk

Lennart Mucke

Makoto Hashimoto

Wolfgang J Wrasidlo

Tamie Chilcote

Kate Dora Games

Brian Spencer

Manuel J Buttini

Igor Flint Tsigelny

Tony Wyss-Coray

Robert Marr

Margaret E Mallory

Hersey Mallory, Legal Representative

Tamie J Chilcote

Dora Kate Games

In alternative embodiments, provided are compositions such as antibodies, e.g., single chain antibodies, that target 3-repeat (3R) Tau for the treatment of neurodegenerative disorders and taupathies such as Alzheimer's Disease (AD), Pick's Disease (PiD) and Fronto-temporal lobar degeneration (FTLD), or any disorder or condition associated with a 3R Tau accumulation, and methods for making and using them. In alternative embodiments, provided are brain-penetrating antibodies that specifically recognize 3R Tau, and methods of using them to treat, ameliorate, prevent or decrease the symptoms of neurodegenerative disorders including taupathies such as Alzheimer's Disease (AD), Pick's Disease (PiD) and Fronto-temporal lobar degeneration (FTLD), or any disorder or condition associated with a 3R Tau accumulation. Provided are methods for diagnosing a neurodegenerative disorder or a taupathy or any disorder or condition associated with a 3R Tau accumulation, and optionally the taupathy is Alzheimer's Disease, Pick's Disease or Fronto-temporal lobar degeneration.

Compositions targeting 3-repeat tau for the treatment of neurodegenerative disorders, and methods for making and using them

The invention provides compositions for increasing the clearance of protein aggregates, and pharmaceutical compositions comprising them, and methods for making and using them, including methods for accelerating protein aggregate clearance in the CNS, e.g., for treating diseases that are characterized by protein aggregation&#x2014;including some degenerative neurological diseases such as Parkinson's disease. In one aspect, the compositions of the invention specifically target synuclein, beta-amyloid and/or tau protein aggregates, and the methods of the invention can be used to specifically prevent, reverse, slow or inhibit synuclein, beta-amyloid and/or tau protein aggregation. In alternative embodiments, the compositions and methods of the invention, are used to treat, prevent, reverse (partially or completely) or ameliorate (including slowing the progression of) degenerative neurological diseases related to or caused by protein aggregation, e.g., synuclein, beta-amyloid and/or tau protein aggregation. In one aspect, compositions and methods of this invention are used to treat, prevent or ameliorate (including slowing the progression of) Parkinson's disease, fronto-temporal dementia (FTD), Alzheimer's Disease (AD), Lewy body disease (LBD) and Multiple system atrophy (MSA).

Compounds for reversing and inhibiting protein aggregation, and methods for making and using them

The present invention relates to a compound of formula (I): Wherein Ris a substituted or unsubstituted aromatic hetero- or homocyclic or a substituted or unsubstituted alicyclic hetero- or homocyclic group; Ris an alkyl group with 1 to 18 carbon atoms or a substituted or unsubstituted cycloalkyl or aryl group; Ris a substituted or unsubstituted aromatic hetero- or homocyclic or a substituted or unsubstituted alicyclic hetero- or homocyclic group; L is a single bond, an alkyl group having 1 to 6 carbon atoms, NHCO, O, S, NHCONH or NHCOO; X, Y and Z are independently O, N, NH, S or CH; W is a single bond or an alkyl group having from 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of said compound or salt.

Compound suitable for the treatment of synucleopathies

The invention provides improved agents and methods for treatment of diseases associated with synucleinopathic diseases, including Lewy bodies of alpha-synuclein in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the Lewy body. The methods are particularly useful for prophylactic and therapeutic treatment of Parkinson's disease.

Prevention and treatment of synucleinopathic and amyloidogenic disease

The invention provides compositions comprising protein aggregation inhibitors, and pharmaceutical compositions comprising them, and methods for making and using them, including methods for preventing, reversing, slowing or inhibiting protein aggregation, e.g., for treating diseases that are characterized by protein aggregation&#x2014;including some degenerative neurological diseases such as Parkinson's disease. In one aspect, the compositions of the invention specifically target synuclein, beta-amyloid and/or tau protein aggregates, and the methods of the invention can be used to specifically prevent, reverse, slow or inhibit synuclein, beta-amyloid and/or tau protein aggregation. In alternative embodiments, the compositions and methods of the invention, are used to treat, prevent or ameliorate (including slowing the progression of) degenerative neurological diseases related to or caused by protein aggregation, e.g., synuclein, beta-amyloid and/or tau protein aggregation. In one aspect, compositions and methods of this invention are used to treat, prevent or ameliorate (including slowing the progression of) Parkinson's disease, Alzheimer's Disease (AD), Lewy body disease (LBD) and Multiple system atrophy (MSA).

Compounds for inhibiting protein aggregation, and methods for making and using them

The methodologies of the present invention demonstrate that a critical balance between pro- and anti-amyloidogenic molecules exists that regulates amyloid formation and cell death in Alzheimer's disease and Parkinson's disease. &#x3b2;-Synuclein, the non-amyloidogenic homologue of &#x3b1;-synuclein, is a negative modulator of &#x3b1;-synuclein and A&#x3b2; aggregation, having neuroprotective properties against &#x3b1;-synuclein and A&#x3b2; neurotoxicity and that &#x3b2;-synuclein and therapeutic agents derived therefrom block amyloidogenesis and neurodegeneration in vivo. The method of the present invention establishes that &#x3b2;-synuclein blocks A&#x3b2; aggregation either by direct inhibition of A&#x3b2; amyloidogenesis or indirectly via either &#x3b1;-synuclein or its 35 a.a. NAC region, inferring neuroprotective characteristics within the effected cells. The generation of a transgenic mouse line and a cell system overexpressing &#x3b1;-synuclein characterizes the mechanisms by which &#x3b2;-synuclein blocks &#x3b1;-synuclein and A&#x3b2; aggregation and that this mechanism offers protection to the cell against amyloid formation as seen in the pathologies of Alzheimer's disease and Parkinson's disease.

Transgenic mice for screening for inhibitors of protein aggregation and methods for making and using them

Treatment and delay of outset of Parkinson's disease

In methods for screening treatments for, and treatment of, neurodegenerative diseases, aggregation in neurons of NACP/&#x3b1;-synuclein is measured and expression of a non-amyloidogenic protein is stimulated in order to reduce the level aggregration. For purposes of screening agents for treatment of neurodegenerative disease, oxidative stress in the neuronal cells is stimulated by introducing a mixture of metal-ions and hydrogen peroxide. Examples of appropriate metals include iron, aluminum, and copper. After introduction of the agent under evaluation for stimulation of expression of non-amyloidogenic protein, the effectiveness is measured by testing for a decrease in the level of aggregation of NACP/&#x3b1;-synuclein. In an exemplary embodiment, the non-amyloidogenic protein is &#x3b2;-synuclein. The aggregation of NACP/&#x3b1;-synuclein is dependent upon the concentration of metal ions in the neuronal cells. In addition, the presence of chelating agents appears to modulate the build-up of NACP/&#x3b1;-synuclein aggregates which are responsible for synaptic and neuronal dysfunction.

Human &#x3b1; synuclein expressing transgenic mice

Alzheimer's disease, Parkinson's disease and Lewy body disease are the most commonly found neurodegenerative disorders in the elderly. The invention is a transgenic mouse that contains two transgenes, human &#x3b1;-synuclein and human amyloid precursor protein, which are responsible for the formation of the neuritic plaques, Lewy bodies and neurodegeneration seen in the above mentioned diseases. The transgenic mouse is an accurate model for disease by both functional and pathological assays.

Transgenic mouse model for neurodegenerative diseases

Transgenic animals, cell lines derived therefrom, and methods for screening for anti-amyloidogenic agents

Method for screening for anti-amyloidogenic properties and method for treatment of neurodegenerative disease

The present invention features non-human transgenic animal models for Alzheimer's disease (AD) and CAA, wherein the transgenic animal is characterized by 1) expression of bioactive transforming growth factor-&bgr;1 (TGF-&bgr;1) or 2) both expression of bioactive TGF-&bgr;1 and expression of a human amyloid &bgr; precursor protein (APP) gene product. The transgenic animals may be either homozygous or heterozygous for these alterations. Bigenic animals are further characterized by development of AD-associated and/or CAA-associated pathology within about two to three months of age, and at about twelve months of age are characterized by a reduced number of neuritic plaques relative to singly transgenic animals. The invention also features methods of screening for biologically active agents that facilitate reduction of &bgr;-amyloid deposits in vivo and methods for facilitating reduction of formation of neuritic plaques in a subject susceptible to AD.

Transgenic mice expressing human APP and TGF-&bgr; demonstrate cerebrovascular amyloid deposits

The present invention features non-human transgenic animal models for Alzheimer's disease (AD) and CAA, wherein the transgenic animal is characterized by 1) overexpression of bioactive transforming growth factor-&bgr;1 (TGF-&bgr;1) or 2) both overexpression of bioactive TGF-&bgr;1 and expression of a human amyloid &bgr; precursor protein (APP) gene product. The transgenic animals may be either homozygous or heterozygous for these alterations. Bigenic animals are further characterized by development of AD-associated and/or CAA-associated pathology within about two to three months of age.

Growing community of inventors

San Diego, CA, United States of America

Eliezer Masliah