Faculty Opinions recommendation of Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy.

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

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Dysregulation of microRNAs in spinal muscular atrophy and the response to antisense oligonucleotide therapy

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.06.040 ◽

2015 ◽

Vol 25 ◽

pp. S194

Author(s):

H. Zhou ◽

F. Catapano ◽

I. Zaharieva ◽

M. Scoto ◽

J. Morgan ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Antisense Oligonucleotide ◽

Muscular Atrophy ◽

Antisense Oligonucleotide Therapy

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Antisense Oligonucleotide Therapies for Neurodegenerative Diseases

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-070918-050501 ◽

2019 ◽

Vol 42 (1) ◽

pp. 385-406 ◽

Cited By ~ 41

Author(s):

C. Frank Bennett ◽

Adrian R. Krainer ◽

Don W. Cleveland

Keyword(s):

Neurodegenerative Diseases ◽

Spinal Muscular Atrophy ◽

Antisense Oligonucleotide ◽

Antisense Oligonucleotides ◽

Muscular Atrophy ◽

Neurological Diseases ◽

Great Promise ◽

Disease Symptoms ◽

Therapeutic Platform ◽

Lateral Sclerosis

Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.

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