Cerebrospinal fluid used to deliver therapeutics for Lou Gehrig's disease to brain

Researchers from the University of California, San Diego have shown that instead of trying to deliver therapeutic agents for neurodegenerative diseases across the highly impermeable blood-brain barrier via the blood, therapeutic molecules known as antisense oligonucleotides can be delivered to the brain and spinal cord through the cerebrospinal fluid (CSF) at doses shown to slow the progression of amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, in rats.

The aggregation of toxic proteins in the central nervous system (CNS) underlies many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS. Several strategies for removing excess proteins from the brain have been tried, but few have been successful due to the impermeability of the protective blood-brain barrier, which prevents substances in the blood from entering brain tissue. In a study in rats appearing online on July 27 in advance of print publication in the August issue of the Journal of Clinical Investigation, Timothy Miller, Richard Smith, and colleagues delivered effective doses of antisense oligonucleotides throughout all brain regions affected in the major neurodegenerative diseases and to all levels of the spinal cord through the CSF. Once produced, CSF circulates from the brain to all regions of the CNS, yielding complete replacement 3 times a day. Exploiting this process and using second-generation oligonucleotides with enhanced tolerability and potency, the authors were able to modulate and deliver effective doses of antisense oligonucleotides. Antisense oligonucleotides to the enzyme superoxide dismutase reduced protein and mRNA levels in the CNS. Delivery of antisense therapy initiated after the onset of symptoms slowed disease progression in a rat model of ALS. This establishes that direct delivery of antisense oligonucleotides through the CSF can be an effective means of treating neurodegenerative diseases when the appropriate toxic protein is known.


TITLE: Antisense oligonucleotide therapy for neurodegenerative disease


Timothy Miller
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 534-7899
Fax: (858) 534-7659
E-mail: [email protected].

Richard A. Smith
Ludwig Institute for Cancer Research, La Jolla, California, USA.
Phone: (858) 455-5463
Fax: (858) 455-1713
E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=25424

Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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