Several different approaches to addressing C9orf72 associated ALS are in the clinical development pipeline today. Two such approaches, using antisense technology, are expected to be in clinical trials in 2018 with a different gene therapy approach, using zinc finger protein technology, slated to begin trials potentially soon after that.
Over the last couple of months, major new information has been released about potential clinical trials on a certain form of familial ALS. An atypical type of genetic mutation in the C9orf72 gene —known as a hexaneucleotide repeat-expansion—are thought to be the most common inherited gene mutation causing ALS. Recently, several small and large drug development companies alike have come out with news of their focus on this specific form of ALS, including the potential for clinical trials to begin before the end of 2018.
WAVE Life Sciences: an antisense approach
Last month, during the closing session of the largest ever gathering of ALS/MND researchers from around the world, Dr. Robert Brown of UMass Medical School provided an overview of his lab’s work characterizing the ability of antisense oligonucleotides (ASOs) developed by WAVE Life Sciences to silence the expression of C9orf72.
In Dr. Brown’s lab, certain ASOs showed ability to knockdown C9orf72 repeat-expansion transcripts when tested in a preclinical model of ALS. His lab also showed that there were reductions in dipeptide repeat proteins (DRPs) and RNA foci, both of which have been identified by others as biological hallmarks of how C9orf72 mutations may be related to neurodegeneration.
In closing his talk, Dr. Brown reported that WAVE Life Sciences was on track to initiate a clinical trial of their lead candidate ASO for C9orf72 mediated ALS, code named WVE-3972-01, by the end of 2018. The ALS Therapy Development Institute (ALS TDI) will continue to monitor the advancement of this trial’s progress, including posting information about its design and enrollment status. To receive email updates on clinical trials of potential treatments for ALS, subscribe to our clinical trial mailing list here.
For more information about WAVE Life Sciences work on WVE-3972-01, click here.
It is important to note that another company, Biogen, has partnered with Ionis Pharmaceutical on advancing ASO approaches into clinical trials in people with ALS. Currently, Biogen is conducting a clinical trial of ASO treatment in people with SOD1 associated ALS. It has been reported that their trial may also begin in 2018, however, no additional details on that are known at this time. As with the WAVE trial, ALS TDI will post information about the Biogen/Ionis trial on its database.
Pfizer and Sangamo: a zinc finger approach
In January, Pfizer announced that it would be expanding its partnership with Sangamo Therapeutics to include ALS. The two companies will collaborate on research using zinc finger protein transcription factors (ZFP-TFs) produced by Sangamo as potential treatment for C9orf72-associated ALS. The two companies previously partnered on launching a clinical trial in a form of hemophila in 2017 using a viral vector approach to gene therapy developed by Sangamo.
Zinc finger proteins are transcription factors which can regulate how a target gene is activated. In other words, ZFP-TFs aim to turn up or down the activity, or expression, of a gene. Sangamo has adapted these proteins into possible therapeutics and has been exploring the potential use of its zinc finger platform to treat ALS. In 2008, Sangamo began a phase 2 clinical trial of a ZFP-TF called SB-509 in people with ALS. SB-509 was designed to encourage an increase in the production of endogenous VEGF, a protein thought to support the health of motor neurons and muscle. While that trial produced encouraging results on muscle function, no additional clinical trials occurred.
A timeline for a clinical trial on the zinc finger approach to targeting C9orf72 is not known at this time. ALS TDI will monitor this collaboration and post information about any upcoming clinical trials in its clinical trial database.
This collaboration between Pfizer and Sangamo is an exciting one as it brings additional pharmaceutical expertise into the global battle against ALS. For more information about the collaboration, click here.
The ALS Therapy Development Institute and C9orf72
ALS TDI has also been hard at work growing our understanding of how the unique repeat-expansion in the C9orf72 gene may lead to neurodegeneration, including the role that DRPs play, understanding how varied the length of the expansions are in people with ALS, and developing cellular models of C9orf72-mediated ALS. At December’s International Symposium co-hosted by ALS TDI in Boston, ALS TDI scientists presented their findings in four important posters, titled:
- An Evaluation of how the Chemical Properties of C9orf72 Dipeptide Repeat Proteins Affect Their Visualization
- Characterization of C9orf72 Dipeptide Repeat Protein Expression and Localization in Transfected Mammalian Cells
- Detection of C9orf72 Allele Expansions in a Cohort of 277 ALS Patients and Control Subjects
- Tail Tip Fibroblast Cell Lines Generated from C9orf72 Transgenic Mice Express Proteins from RAN Translation