The United States of America, As Represented by the Secretary, Department of Health and Human Services

University of Michigan

Progeria Research Foundation, Inc.

Other

University System of Maryland

Sarepta Therapeutics, Inc.

The University of North Carolina at Chapel Hill

Research Foundation for Mental Hygiene, Inc.

Hsc Research Development Corporation

The University of Texas System

The United States of America As Represented by the Department of Health

Ramot University Authority for Applied Research and Industrial Development Limited

Ramot University Authority for Applied Research and Industrial

The Board of Regents Acting for and on Behalf of the University of

Francis S Collins

Leslie B Gordon

Mitchell L Drumm

Johanna Rommens

Ryszard M Kole

Kan Cao

John R Riordan

Manuel Buchwald

Michael R Erdos

Bat-Sheva Kerem

Michael C Iannuzzi

Lap-Chee Tsui

Channing J Der

Michael W Glynn

Adrienne Cox

B Maria H Eriksson

Thomas Glover

Brian C Capell

Yosef Shiloh

Danilo A Tagle

W Ted Brown

Mark S Chee

Richard Keith Bestwick

Joseph G Hacia

Michael J Siciliano

Pu Liu

David H Gutmann

Lone B Andersen

Douglas A Marchuk

Margaret R Wallace

David Claxton

James M Wilson

Lance A Liotta

Michael R Emmert-Buck

Darrell Orlyn Ricke

Zhengping Zhuang

Allen M Spiegel

Robert I Richards

William Ted Brown

Nathan Fischel-Ghodsian

Irina A Lubensky

Deborah L Gumucio

Settara Chandrasekharappa

P Paul Liu

Trevor Blake

Siradanahalli Guru

Ramen Sood

Zuoming Deng

Pachiappan Manickam

Michael Centola

Ivona Aksentijevichh

Larisa V Debelenko

Daniel L Kastner

Norman A Doggett

Mordechai Pras

Sunita K Agarwal

A Lee Burns

Stephen J Marx

Tsui Lap-Chee

David C Dawson

Daniel J Wilkinson

Ted W Brown

Adrienne D c/o Dept Radiation Oncology Cox

Channing J c/o Lineberger CompCancer Ctr Der

Maria B H Eriksson

Provided are LMNA-targeted antisense oligonucleotides for reducing expression of one or more aberrantly spliced LMNA mRNA isoforms that encode progerin.

Oligonucleotide analogues targeting human LMNA

Provided are methods of treatment in subjects having progeroid diseases and related conditions which rely upon LMNA-targeted antisense oligonucleotides for reducing expression of one or more aberrantly spliced LMNA mRNA isoforms that encode progerin.

Methods for treating progeroid laminopathies using oligonucleotide analogues targeting human LMNA

Disclosed herein are point mutations in the LMNA gene that cause HGPS. These mutations activate a cryptic splice site within the LMNA gene, which leads to deletion of part of exon 11 and generation of a mutant Lamin A protein product that is 50 amino acids shorter than the normal protein. In addition to the novel Lamin A variant protein and nucleic acids encoding this variant, methods of using these molecules in detecting biological conditions associated with a LMNA mutation in a subject (e.g., HGPS, arteriosclerosis, and other age-related diseases), methods of treating such conditions, methods of selecting treatments, methods of screening for compounds that influence Lamin A activity, and methods of influencing the expression of LMNA or LMNA variants are also described. Oligonucleotides and other compounds for use in examples of the described methods are also provided, as are protein-specific binding agents, such as antibodies, that bind specifically to at least one epitope of a Lamin A variant protein preferentially compared to wildtype Lamin A, and methods of using such antibodies in diagnosis, treatment, and screening. Also provided are kits for carrying out the methods described herein.

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Although it can be farnesylated, the mutant lamin A protein expressed in Hutchinson Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called 'progerin') that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with farnesyltransferase inhibitors.

Farnesyltransferase inhibitors for treatment of laminopathies, cellular aging and atherosclerosis

Although it can be farnesylated, mutant lamin A expressed in Hutchinson Gilford Progeria Syndrome cannot be defarnesylated; the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein ('progerin') that alters normal lamin A function as a dominant negative, and assumes its own aberrant function through its association with the nuclear membrane. Retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) will inhibit formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with FTIs.

Disclosed herein are point mutations in the LMNA gene that cause HGPS. These mutations activate a cryptic splice site within the LMNA gene, which leads to deletion of part of exon 11 and generation of a mutant Lamin A protein product that is 50 amino acids shorter than the normal protein. In addition to the novel Lamin A variant protein and nucleic acids encoding this variant, methods of using these molecules in detecting biological conditions associated with a LMNA mutation in a subject (e.g., HGPS, arteriosclerosis, and other age-related diseases), are also described. Oligonucleotides and other compounds for use in examples of the described methods are also provided, as are protein-specific binding agents, such as antibodies, that bind specifically to at least one epitope of a Lamin A variant protein preferentially compared to wildtype Lamin A, and methods of using such antibodies in diagnosis, treatment, and screening.

LMNA gene and its involvement in Hutchinson-Gilford Progeria Syndrome (HGPS) and arteriosclerosis

Although it can be farnesylated, the mutant lamin A protein expressed in Hutchison Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called 'progerin') that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with farnesyltransferase inhibitors.

The invention relates to the discovery of a novel tumor suppressor gene which is associated with multiple endocrine neoplasia type 1. The gene has been designated MEN1 and the gene product is menin. The absence of this protein and associated mutations in the corresponding gene have been identified in individuals suffering from multiple endocrine neoplasia type 1. The identification of this marker for multiple endocrine neoplasia type 1 has diagnostic uses as well as for gene therapy.

The cystic fibrosis gene and its gene product are described for both the normal and mutant forms. The genetic and protein information is used in developing DNA diagnosis, protein diagnosis, carrier and patient screening, drug and gene therapy, cloning of the gene and manufacture of the protein, and development of cystic fibrosis affected animals.

Cystic fibrosis gene

Growing community of inventors

Rockville, MD, United States of America

Francis S Collins