University of Massachusetts

Neil Aronin

Anastasia Khvorova

Phillip D Zamore

Julia Alterman

Edith L Pfister

Matthew Hassler

Reka Haraszti

Christian Mueller

Anton A Turanov

Mehran Nikan

Maire Osborn

Andrew Coles

Reka Agnes Haraszti

Ken Yamada

Faith Conroy

Marie Cecile Didiot

Annabelle Biscans

Sarah Rinde Oikemus

Michael Harry Brodsky

The present invention contemplates-allele-specific gene editing based on targeting a heterozygous single nucleotide polymorphism (SNP) in a protein coding sequence associated with a genetic disease. The data shown herein demonstrates that the outcome of such gene editing creates a nonesense mutation that results in a marked and selective reduction of mutant protein without affecting wild type protein expression. Expression of a single CRISPR-Cas9 nuclease in neurons generated a high frequency of mutations in the targeted HD allele that included both small insertion/deletion mutations and viral vector insertions. Thus, as disclosed herein, allele-specific targeting of InDel and insertion mutations to heterozygous coding SNPs provides a feasible approach to inactivate autosomal dominant mutations that cause genetic disease.

Allele-specific inactivation of mutant HTT via gene editing at coding region single nucleotide polymorphisms

Provided herein are self-delivering oligonucleotides that are characterized by efficient RISC entry, minimum immune response and off-target effects, efficient cellular uptake without formulation, and efficient and specific tissue distribution.

Fully stabilized asymmetric siRNA

Bioactive conjugates for oligonucleotide delivery

Novel artificial exosomes and methods for producing novel artificial exosomes are provided. Methods of delivering cargo molecules to a cell using artificial exosomes are also provided.

Artificial exosome composition and related methods

Novel oligonucleotides that enhance silencing of the expression of a gene containing a single nucleotide polymorphism (SNP) relative to the expression of the corresponding wild-type gene are provided. Methods of using novel oligonucleotides that enhance silencing of the expression of a gene containing a SNP relative to the expression of the corresponding wild-type gene are provided.

Modified oligonucleotides targeting SNPs

Aspects of the disclosure relate to compositions and methods useful for treating Huntington's disease. In some embodiments, the disclosure provides interfering nucleic acids (e.g., artificial miRNAs) targeting the huntingtin gene (HTT) and methods of treating Huntington's disease using the same.

AAV treatment of Huntington's disease

Provided herein are conjugated oligonucleotides that are characterized by efficient and specific tissue distribution.

Conjugated oligonucleotides

In one aspect, the invention relates to a method of loading exosomes with oligonucleotide cargo, by incubating an oligonucleotide comprising one or more hydrophobic modifications with a population of exosomes for a period of time sufficient to allow loading of the exosomes with the oligonucleotide. Exosomes loaded with hydrophobically modified oligonucleotide cargo, and uses thereof, are also provided.

Exosomal loading using hydrophobically modified oligonucleotides

The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington's disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease.

RNA interference for the treatment of gain-of-function disorders

This disclosure relates to novel huntingtin targets. Novel oligonucleotides for the treatment of Huntington's disease are also provided.

Growing community of inventors

Newtonville, MA, United States of America

Neil Aronin