Pathologies associated with genetic alterations present in both fALS and sALS patients involve consequences stemming from the transcription of mutated genes. Subsequent translation of mutated transcripts can produce proteins demonstrating either gain or loss of function, mislocalization within the cell or a combination of both.

Recent evidence has reinforced the effectiveness of antisense oligonucleotides (ASOs) as a viable treatment modality through their ability to address these effects at the translation stage. ASOs are short, synthetic ssRNAs designed to selectively bind a complementary sequence present in specific RNAs. Their clinical utility is highlighted by an ability to be administered intrathecally, which promotes access to targets associated with neurodegeneration in both the brain and spinal cord.

Since the discovery of SOD1 as the first ALS-associated gene, reported in Nature by Robert Brown, MD, PhD—formerly of Mass General—and his collaborators, significant effort has focused on the effects accompanying its mutations and the wide variability in their clinical presentation. Among those efforts was a Phase I/II conducted through the NEALS Consortium in 2016 that published its findings in The New England Journal of Medicine (NEJM), showing that the dosing strategy for an ASO targeting SOD1 mRNA (Tofersen) to reduce the synthesis of misfolded SOD1 variants implicated in ALS pathogenesis.

The subsequent phase III trial, results summarized in the NEJM, and its OLE study reported the following effects of intrathecal administration of Tofersen to SOD1 ALS patients:

Lower levels of SOD1 protein
Significantly lower levels of a biomarker of axonal damage (neurofilament light chain), suggesting a substantial slowing of neurodegeneration
Stabilized or improved clinical presentations during the longer-term follow-up period

As a co-principal investigator on the trial, Dr. Cudkowicz explains that although the primary endpoints were not met according to the six-month timeline, the longer-term outcomes are very encouraging. In fact, they are still following patients that participated in the Phase I trial.

“Advances in ASO technology along with these findings reinforce my early belief in their potential as an effective gene therapy for ALS patients,” she says. “Our data suggest that although this strategy may require longer timelines, the outcomes appear largely in favor of the patients.”

联系我们

手机通话

邮箱

地址识别

发消息给我们