The present disclosure provides transposon-based methods of genetic editing in pluripotent stem cells, and methods of lineage specific differentiation of such edited pluripotent stem cells into floor plate midbrain progenitor cells, determined dopamine (DA) neuron progenitor cells, and/or DA neurons, or into glial cells, such as microglial cells, astrocytes, oligodendrocytes, or ependymocytes. Also provided are compositions and uses thereof, such as for treating neurodegenerative diseases and conditions, including Parkinson's disease.

Among the various aspects of the present disclosure is the provision of compositions and methods for selectively reducing pathogenic isoforms (e.g., DNAJB6) in a subject having a neuromuscular disorder. An aspect of the present disclosure provides for selectively reducing DNAJB6 in a subject having a neuromuscular disorder (e.g., limb-girdle muscular dystrophy D1 (LGMD-D1)) comprising administering an amount of a DNAJB6-targeting antisense oligonucleotide (ASO) sufficient to reduce the expression of DNAJB6 compared to the subject prior to being administered the DNAJB6-targeting ASO.

The present invention provides iRNA agents, e.g., double stranded iRNA agents, that target the transthyretin (TTR) gene and methods of using such iRNA agents for treating or preventing TTR-associated ocular diseases.

Among other things, the present disclosure provides designed PNPLA3 oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide improved single-stranded RNA interference and/or RNase H-mediated knockdown. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or N patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., RNA interference (RNAi) activity, stability, delivery, etc. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in RNA interference and/or RNase H-mediated knockdown.

Featured are methods for the treatment or prevention of spinal muscular atrophy. Effective dosage regimens are specified. Biomarkers and kits are also provided.

The present disclosure relates to using CRISPR-based methods to perform gene editing to correct frame shift mutations in alleles with detectable phenotypes, and to correct aneuploidies.

Provided are compositions and methods used for precise template-free correction of BRCA1 mutation in human cells via genome editing. The method involves modifying DNA that includes a BRCA1-5382-InsC mutation by introducing into cells comprising the BRCA1-5382-InsC a Cas enzyme and a guide RNA. A guide RNA that produces improved results relative to other guide RNAs is provided. Also provided are modified stem cells that contain an introduced BRCA1-5382-InsC mutation.

Provided are methods for editing RNA by introducing a deaminase-recruiting RNA in a host cell for deamination of an adenosine in a target RNA, deaminase-recruiting RNAs used in the RNA editing methods, compositions and kits comprising the same.

Provided herein are compositions and methods of using base editors comprising a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain in conjunction with a guide polynucleotide. Also provided herein are base editor systems for editing nucleobases of target nucleotide sequences.

The present disclosure provides methods of treating subjects having a liver disease with a CAMP Responsive Element Binding Protein 3 Like 3 (CREB3L3) inhibitor, and methods of identifying subjects having an increased risk of developing a liver disease.