**3.4 Antisense therapy in neurological disorders**

Antisense drugs are being evaluated for multiple neurological diseases and are administered systemically into the cerebrospinal fluid (CSF) that surrounds the brain. Antisense oligonucleotides cannot cross the intact blood–brain barrier efficiently; therefore, they are directly introduced into the CSF or parenchyma to treat brain or spinal cord diseases. Thus, neurological diseases can be approached using different antisense mechanisms and oligonucleotide designs, with single-stranded antisense oligonucleotides and siRNAs used for local therapy [6]. **Duchenne muscular dystrophy** is a progressive, severely disabling, and ultimately lethal neuromuscular disease caused by point mutations, insertions, or chromosomal rearrangements in the dystrophin gene resulting in truncated protein or loss of transcript through nonsense-mediated decay [25]. Because of multiple genomic alterations in Duchenne muscular dystrophy, no single oligonucleotide will address all forms of the disease [6, 25]. Antisense oligonucleotides designed to promote skipping of exon 51 are the most advanced in clinical trials, and the modified phosphorothioate oligonucleotide drug, eteplirsen, is under regulatory review for marketing approval. Additional antisense drugs are currently under development

for targeting other exons, which will broaden the treatment of the patient population. **Myotonic dystrophy type 1 (DM1)** is a multisystemic disease caused by a triplet repeat expansion (CTG) in the 3′ untranslated region of myotonic dystrophy protein kinase (DMPK) gene [26]. IONIS-DMPK-2.5Rx is a chimeric antisense oligonucleotide and is currently under a randomized controlled study trail in DM1 patients. **Transthyretin amyloidosis** is a form of systemic amyloidosis caused by misfolded transthyretin protein (TTR), in multiple tissues, including peripheral nerves, the gastrointestinal tract, and the heart [27]. Three different antisense drugs, IONIS-TTRRx, RNase H–dependent, and patisiran, are currently in development for the treatment of TTR amyloidosis, as well as for both familial amyloid polyneuropathy and cardiomyopathy [28]. **Spinal muscular atrophy (SMA)**, a progressive motor neuron disease, usually occurs in infancy or childhood caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene [29]. Nusinersen drug is a fully modified oligonucleotide designed to bind to a specific sequence in intron 7 of the SMN1 and 2 pre-mRNAs, enhancing exon 7 inclusion and increasing the production of SMN protein [30, 31] which is under review for market authorization. **Huntington's disease (HD)** is an autosomal dominant neurodegenerative disorder resulting from an expanded CAG repeat in the huntingtin (HTT) gene, which causes a toxic gain of function due to an expanded polyglutamine tract in the resulting protein. Antisense oligonucleotide designed to lower total HTT has been shown to provide a prolonged improvement in HD, and the drug is in clinical trial phase [30, 31].
