ROGER A WILLIAMSON, MD
Medical Practice at Hawkins Dr, Iowa City, IA

2001001, Aug 23, 2001

Jan 4, 2001

09/754765

Kevin Campbell - Iowa City IA, US
Ramon Coral - Iowa City IA, US
Ronald Cohn - Iowa City IA, US
Roger Williamson - Iowa City IA, US
Madeleine Durbeej - Iowa City IA, US

A01K067/027

800/018000, 800/003000

Disclosed within is a mouse, and cells derived therefrom, which are homozygous for a disrupted -sarcoglycan gene, the disruption in said gene having been introduced into the mouse or an ancestor of the mouse at an embryonic stage. Said disruption prevents the synthesis of functional -sarcoglycan in cells of the mouse and results in the mouse having a reduced amount of - and -sarcoglycan and sarcospan, and a disruption of the sarcoglycan-sarcospan complex in smooth muscle of the mouse. Said disruption also results in a reduced amount of sarcospan, -, -, -, and -sarcoglycan in the sarcolemma of skeletal and cardiac muscles of the mouse, compared to the amounts of said components in a mouse lacking disrupted -sarcoglycan genes. Preferred specific disruptions of the -sarcoglycan gene are listed. Also disclosed is a mouse, and cells derived therefrom, which are homozygous for a disrupted -sarcoglycan gene, the disruption in said gene having been introduced into the mouse or an ancestor of the mouse at an embryonic stage. The disruption prevents the synthesis of functional -sarcoglycan in cells of the mouse and results in the mouse having a reduced amount of - and -sarcoglycan and sarcospan and -dystroglycan in smooth muscle of the mouse. The disruption also results in a disruption of the sarcoglycan-sarcospan complex in smooth muscle of the mouse, and a reduced amount of sarcospan, , , - and -sarcoglycan in the sarcolemma of skeletal and cardiac muscles of the mouse, compared to the amounts of the components in a mouse lacking disrupted -sarcoglycan genes. Preferred specific disruptions of the -sarcoglycan gene are listed. A method for treating mammalian autosomal recessive limb-girdle muscular dystrophy type 2F in an individual is also disclosed. The method comprises, providing an expression vector which encodes a wild-type form of -sarcoglycan, and introducing the expression vector into skeletal and smooth muscle tissue of the individual under conditions appropriate for expression of the wild-type form of -sarcoglycan in said tissues. Examples of expression vectors for use in this method are adenovirus expression vector, a gutted adenovirus expression vector, and an adeno-associated expression vector. Also disclosed are methods for treating mammalian autosomal recessive limb-girdle muscular dystrophy type 2E, and type 2F, in an individual. The methods comprise, providing an expression vector which encodes a wild-type form of -sarcoglycan, or -sarcoglycan, respectively, and introducing the expression vector into skeletal and smooth muscle tissue of the individual under conditions appropriate for expression of the wild-type form of the sarcoglycan gene in said tissues. The -sarcoglycan deficient, and -sarcoglycan deficient mice of the present invention are useful in identifying therapeutic compounds for treatment of an individual diagnosed with -sarcoglycan-deficient limb-girdle muscular dystrophy, and -sarcoglycan-deficient limb-girdle muscular dystrophy, respectively. A therapeutic method for treating ischemic heart disease caused by reduced expression of the sarcoglycan-sarcospan complex in vascular smooth muscle cells of an individual is also provided. The method comprises contacting the vascular smooth muscle cells of the individual with a vascular smooth muscle relaxant, such as Nicorandil. This method is also useful for preventing ischemic injury in skeletal and cardiac muscle of an individual caused by reduced expression of the sarcoglycan-sarcospan complex in the vascular smooth muscle cells of the individual. The method is also useful for treating mammalian autosomal recessive limb-girdle muscular dystrophy type 2F or type 2E in an individual. Other methods provided include a method for identifying a therapeutic compound for the treatment of ischemic heart disease in an individual caused by reduced expression of the sarcoglycan-sarcospan complex in the vascular smooth muscle cells of the individual, and also a method for identifying a therapeutic compound for the prevention of ischemic injury in skeletal and cardiac muscle of an individual which is caused by reduced expression of the sarcoglycan-sarcospan complex in vascular smooth muscle cells of the individual.

6201168, Mar 13, 2001

Aug 20, 1999

9/378418

Kevin P. Campbell - Iowa City IA
Ramon Coral - Iowa City IA
Ronald Cohn - Iowa City IA
Roger Williamson - Iowa City IA
Madeleine Durbeej - Iowa City IA

University of Iowa Research Foundation - Iowa City IA

A01K 67027, G01N 3300

800 18

Disclosed is a mouse, cells derived therefrom, and methods for using the mouse, the mouse being homozygous for a disrupted. delta. -sarcoglycan gene, the disruption in the gene having been introduced into the mouse or an ancestor of the mouse at an embryonic stage. The disruption prevents the synthesis of functional. delta. -sarcoglycan in cells of the mouse and results in the mouse having a reduced amount of. beta. - and. epsilon. -sarcoglycan and sarcospan, and a disruption of the sarcoglycan-sarcospan complex in smooth muscle of the mouse. Also disclosed is a mouse, cells derived therefrom, and methods for using the mouse, the mouse being homozygous for a disrupted. beta. -sarcoglycan gene, the disruption in the gene having been introduced into the mouse or an ancestor of the mouse at an embryonic stage. The disruption prevents the synthesis of functional. beta. -sarcoglycan in cells of the mouse and results in the mouse having a reduced amount of. delta. -and. epsilon.

6207878, Mar 27, 2001

Oct 21, 1999

9/422762

Kevin P. Campbell - Iowa City IA
Connie Lebakken - Iowa City IA
Rachelle Crosbie - Iowa City IA
Roger Williamson - Iowa City IA

University of Iowa Research Foundation - Iowa City IA

A01K67/027, 7, G01N33/00

800 18

Disclosed is a transgenic knockout mouse whose genome has a homozygous disruption in its endogenous sarcospan gene, wherein the disruption prevents the synthesis of functional sarcospan in cells of the mouse. The mouse is characterized as exhibiting from 1. 4 to 6. 8 fold larger epididymal fat pad deposits as compared to the epididymal fat pad deposits of a wild type mouse. Methods for production of the mouse are presented. Also disclosed are cells derived from the transgenic knockout mouse. The mouse can be used in a method for identifying therapeutic agents for the treatment of an individual diagnosed with a metabolic disorder associated with a reduction or loss of expression of wild-type sarcospan. An example of such a disorder is weight gain in the individual associated with a reduction or loss of expression of wild-type sarcospan. These specific methods are also provided.

6262035, Jul 17, 2001

Oct 1, 1998

9/164664

Kevin P. Campbell - Iowa City IA
Kathleen H. Holt - Corlville IA
Franck Duclos - Iowa City IA
Leland E. Lim - Iowa City IA
Volker Straub - Essen IA
Beverly Davidson - Iowa City IA
Roger Williamson - Iowa City IA

University of Iowa Research Foundation - Iowa City IA

A01N 4304, C12N 1500, C12N 1563

514 44

Disclosed is a method for treating a patient suffering from the disease sarcoglycan-deficient limb-girdle muscular dystrophy by gene replacement therapy. Sarcoglycan gene replacement therapy produces extensive long-term expression of the sarcoglycan species which restores the entire sarcoglycan complex, results in the stable association of alph. alpha. -dystroglycan with the sarcolemma, and eliminates the morphological markers of limb-girdle muscular dystrophy. In another aspect, the invention relates to a method for determining a specific defective sarcoglycan species in the tissue of a patient. The method involves culture of muscle cells obtained from the patient, and the independent introduction of expression vectors encoding each of the sarcoglycan species,. alpha. ,. beta. ,. gamma. , and. delta. , into the cultured cells with subsequent assaying for restoration of the dystrophin-glycoprotein complex. In another aspect, the invention relates to a mouse, and cells derived therefrom, homozygous for a disrupted. alpha.

6083911, Jul 4, 2000

Dec 10, 1998

9/208707

Kevin P. Campbell - Iowa City IA
Michael Henry - Iowa City IA
Hiroki Yamada - Iowa City IA
Roger Williamson - Iowa City IA
Wei Cao - San Diego CA
Michael Oldstone - La Jolla CA

University of Iowa Research Foundation - Iowa City IA

A61K 3534, A61K 3816

514 8

Disclosed is a method for inhibiting the binding of an arenavirus to a cellular receptor. The method involves providing, in soluble form, a reagent comprising. alpha. -dystroglycan or a portion thereof, the reagent being characterized by the ability to bind to the arenavirus thereby inhibiting the binding of the arenavirus to the cellular receptor. The reagent is contacted with an arenavirus particle prior to infection of a cell by the arenavirus particle. Also disclosed are methods for treating an arenavirus infection in a patient and preventing an arenavirus infection in an individual at risk. These methods involve providing a therapeutic composition comprising. alpha. -dystroglycan or a portion thereof which is characterized by the ability to bind to arenaviruses, thereby inhibiting the binding of arenaviruses to a cellular receptor; and administering the composition to the patient or individual at risk. Arenaviruses to which the methods of the present invention apply include, without limitation, Lymphocyte Choriomeningitis Virus, Lassa fever virus, Mobala, and Oliveros. In another aspect, the disclosure relates to an embryonic stem cell line, and cells derived therefrom, which is homozygous for a disrupted dystroglycan gene, wherein the disruption prevents the synthesis of functional dystroglycan in the cells.

6194633, Feb 27, 2001

Jan 26, 1998

9/013687

Gary A. Koretzky - North Liberty IA
James L. Clements - Iowa City IA
Roger Williamson - Iowa City IA

University of Iowa Research Foundation - Iowa City IA

A01K 6700, G01N 3300, C12N 1500

800 18

A nonhuman animal having somatic and germ cells in which at least one allele of an endogenous SLP-76 gene is functionally disrupted is provided. The animal may be heterozygous or, more preferably, homozygous for the SLP-76 gene disruption and is preferably a mouse. In homozygous animals, the percentage of peripheral T cells is substantially decreased compared to wildtype animals, whereas the percentage of B cells and macrophages in the periphery is substantially normal, indicating that SLP-76 disruption causes a profound block in T cell development. The animals of the invention can be used, for example, as controls to evaluate the efficacy of SLP-76 inhibitors and to identify disease conditions that can be treated with SLP-76 inhibitors. A transgenic nonhuman animal having a functionally disrupted endogenous SLP-76 gene but which has been reconstituted with an exogenous SLP-76 transgene (e. g. , a human SLP-76 gene or a SLP-76 gene whose expression in targeted to a particular cell population) is also provided.