12:00 AM
Nov 07, 2013
 |  BC Innovations  |  Cover Story

ALS antisense oligonucleotides

Isis Pharmaceuticals Inc. has teamed up with a trio of academic groups to develop antisense therapeutics for the largest subset of patients with amyotrophic lateral sclerosis,1-3 and all three teams have converged on a common mechanism of neurotoxicity caused by carrying hexanucleotide repeat expansions in the C9orf72 gene. Antisense oligonucleotides targeting the repeats decreased the toxicity in vitro. The teams now need to determine whether the reduced toxicity correlates with decreased neurodegeneration in patients.

Amyotrophic lateral sclerosis (ALS) is a neurological disorder that involves muscle wasting, stiffness and spasticity due to loss of motor neurons. ALS often overlaps with frontotemporal lobar dementia (FTLD), a disease that involves neuronal degeneration in the frontal and temporal cortices.

Both diseases can occur as inherited familial disorders or sporadically with no known familial link.

The GGGGCC repeat expansion in the first intron of C9orf72 (chromosome 9 open reading frame 72) is the most common genetic cause of ALS.4,5 It has been identified in more than 40% of familial ALS and FTLD cases and in at least 8% of sporadic cases.

Nevertheless, the mechanistic link between the expansion and neuronal toxicity remained a mystery.

To identify the root causes of neurotoxicity in C9orf72 ALS and FTLD, Isis teamed up with three academic teams.

"Each lab is doing unique experiments, and we were fortunate that the results from the different labs triangulated. We have consistently seen that the antisense oligonucleotides reverse RNA foci formation and reverse the transcriptional problems seen in ALS," said C. Frank Bennett, SVP of research at Isis.

RNA foci are long RNA repeat expansions that have folded into stable structures. The foci sequester RNA-binding proteins required for normal cellular transcription and splicing. The result is disruption in normal gene expression and protein function.


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