Provided are compounds, methods, and pharmaceutical compositions for modulating SCN1A RNA and/or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a developmental or epileptic encephalopathic disease, such as Dravet Syndrome. Such symptoms include seizures, sudden unexpected death in epilepsy, status epilepticus, behavioral and developmental delays, movement and balance dysfunctions, orthopedic conditions, motor and cognitive dysfunctions, delayed language and speech issues, visual motor integration dysfunctions, visual perception dysfunctions, executive dysfunctions, growth and nutrition issues, sleeping difficulties, chronic infections, sensory integration disorders, and dysautonomia.

Provided is a nucleoside derivative represented by the following formula (1):

##STR00001##

or a salt thereof, wherein R.sup.1 represents an alkoxy group, a hydrogen atom or a halogen atom; R.sup.2 and R.sup.4, which may be the same as or different from each other, each represents a hydrogen atom, a protective group for a hydroxyl group, a phosphate group, a protected phosphate group, or —P(═O).sub.nR.sup.5R.sup.6 in which n represents 0 or 1, R.sup.5 and R.sup.6, which may be the same as or different from each other, each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a mercapto group, a protected mercapto group, an alkoxy group, a cyanoalkoxy group, an amino group, or a substituted amino group, provided that when n is 1, both R.sup.5 and R.sup.6 cannot be the hydrogen atom at the same time; R.sup.3 represents —(CH.sub.2).sub.mNHR.sup.7 in which m represents an integer of 1 to 6, R.sup.7 represents a hydrogen atom, an alkyl group, an alkenyl group or a protective group for an amino group; and B represents a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purin-9-yl group, or a substituted 2-oxo-pyrimidin-1-yl group.

Provided is a nucleoside derivative represented by the following formula (1):

##STR00001##

or a salt thereof, wherein R.sup.1 represents an alkoxy group, a hydrogen atom or a halogen atom; R.sup.2 and R.sup.4, which may be the same as or different from each other, each represents a hydrogen atom, a protective group for a hydroxyl group, a phosphate group, a protected phosphate group, or —P(═O).sub.nR.sup.5R.sup.6 in which n represents 0 or 1, R.sup.5 and R.sup.6, which may be the same as or different from each other, each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a mercapto group, a protected mercapto group, an alkoxy group, a cyanoalkoxy group, an amino group, or a substituted amino group, provided that when n is 1, both R.sup.5 and R.sup.6 cannot be the hydrogen atom at the same time; R.sup.3 represents —(CH.sub.2).sub.mNHR.sup.7 in which m represents an integer of 1 to 6, R.sup.7 represents a hydrogen atom, an alkyl group, an alkenyl group or a protective group for an amino group; and B represents a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purin-9-yl group, or a substituted 2-oxo-pyrimidin-1-yl group.

The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a leucine-rich repeat kinase 2 (LRRK2) gene, as well as methods of inhibiting expression of a LRRK2 gene and methods of treating subjects having a LRRK2-associated disease or disorder, e.g., Parkinson's disease, using such dsRNAi agents and compositions.

The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a leucine-rich repeat kinase 2 (LRRK2) gene, as well as methods of inhibiting expression of a LRRK2 gene and methods of treating subjects having a LRRK2-associated disease or disorder, e.g., Parkinson's disease, using such dsRNAi agents and compositions.

The invention provides an antisense oligonucleotide capable of controlling ATN1 gene expression and treating dentatorubral-pallidoluysian atrophy. An inventive compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence including at least 8 contiguous nucleobases that are complementary to a transcript of ATN1, or a pharmacologically acceptable salt thereof.

The invention provides an antisense oligonucleotide capable of controlling ATN1 gene expression and treating dentatorubral-pallidoluysian atrophy. An inventive compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence including at least 8 contiguous nucleobases that are complementary to a transcript of ATN1, or a pharmacologically acceptable salt thereof.

The present invention provides a compound or a pharmaceutically acceptable salt thereof containing a modified oligonucleotide with a length of 8 to 80 consecutive nucleosides, in which the modified oligonucleotide has a nucleobase sequence containing at least 8 consecutive nucleobases contained in a nucleobase sequence of any one of SEQ ID NOs: 3 to 73. With the compound or a pharmaceutically acceptable salt thereof, it is possible to treat a disease or a condition against which inhibition of CALM2 gene expression by controlling of the CALM2 gene expression is effective (particularly, congenital long QT syndrome).

The present invention provides a compound or a pharmaceutically acceptable salt thereof containing a modified oligonucleotide with a length of 8 to 80 consecutive nucleosides, in which the modified oligonucleotide has a nucleobase sequence containing at least 8 consecutive nucleobases contained in a nucleobase sequence of any one of SEQ ID NOs: 3 to 73. With the compound or a pharmaceutically acceptable salt thereof, it is possible to treat a disease or a condition against which inhibition of CALM2 gene expression by controlling of the CALM2 gene expression is effective (particularly, congenital long QT syndrome).

Disclosed herein include guide RNA (gRNA), such as single gRNA (sgRNA), and compositions thereof, comprising 2′-O-methyldithiomethyl modified sugar moieties which can be reduced to 2′-O-methanethiol groups in the reducing environment of cells and then converted (e.g., spontaneously converted) to 2′-OH. The resultant gRNA can bind to and direct the activity of an RNA-guided endonuclease (e.g., Cas9).