Repeated expansion of DNA in the C9orf72 region causes amyotrophic lateral sclerosis and frontotemporal dementia. The protein C9orf72 is localized in many regions of the brain, in the cytoplasm of neurons as well as in the presynaptic terminals. This protein regulates endosomal trafficking and autophagy in neuronal cells and primary neurons. Mutations causing repeat reading frames of this gene were discovered in 2011 by two independent research teams, led by Rosa Rademakers of Mayo Clinic and Bryan Traynor of the National Institutes of Health.
Preventive treatment with antisense oligonucleotides improved the disease in C9orf72 mouse models but would require regular intrathecal injection. Active vaccination is a promising approach to reduce the severity of the disease or even prevent ALS and FTD in people with the C9orf72 mutation.
As in other FTLD / ALS variants, the intracellular inclusions characteristic of improperly folded proteins define the pathology C9orf72. The proteins in these C9orf72-linked inclusions were identified in 2013 by the team of Dieter Edbauer in Munich in Germany.
They found that most of these characteristic inclusions contain proteins with repeats of poly-(Gly-Ala) dipeptide and, to a lesser extent poly-(Gly-Pro) and poly-(Gly-Arg) dipeptides (collectively called Poly-GA repeats in this text).
As we have often pointed out, the genetic origin of familial forms of ALS in the elderly raises questions. Why is this delay of several decades, when similar neurodegenerative diseases like SMA, strike children from an early age? One can also ask how a genetic origin of the disease can explain the progressive nature of ALS, how can it first attack only one hand or ankle and then gradually spread to the whole body, while all cells in the body have the same genetic heritage?
In 2016 Westergard et al. examined cell-to-cell propagation of C9orf72-linked dipeptide repeat proteins in vitro and in animal models. Westergaard and colleagues suggested that transcellular transmission may explain the progressive neurodegeneration of these diseases. This article was highly appreciated by the scientific community, but other explanations were also proposed and a consensus was not reached.
A particular case of this problem concerns the relationship between the pathology specific to C9orf72 and the pathology TDP-43. Understanding this relationship could greatly improve our knowledge of these two diseases (ALS and FTD), or even why not indicate a therapeutic path.
Scientists in Dieter Edbauer's team, recently showed that the extra cellular circulation of Poly-GA repeats promotes poor cytoplasmic localization and aggregation of TDP‐43.
Since the Poly-GA repeats are transmitted between cells, researchers from Dieter Edbauer's team studied the therapeutic potential of antibodies against Poly-GA repeats by vaccinating mice modeling C9orf72 ALS.
To overcome the poor immunogenicity, the researchers used ovalbumin as an adjuvant, which induced a strong response against Poly-GA repeats. Vaccine immunization largely saved motor function in 149-CFP transgenic mice.
Analysis of the transcriptome showed less neuroinflammation in mice, which was corroborated by a semi-quantitative and morphological analysis of microglia / macrophages. In addition, the poor cytoplasmic localization of TDP‐43 and the light chain levels of neurofilaments have been reduced, suggesting that neuroaxonal damage is reduced.
These data suggest that immunotherapy may be a viable primary prevention strategy for ALS / FTD in carriers of the C9orf72 mutation.
An immunogenic carrier protein such as ovalbumin can significantly improve the immunogenicity of the Poly-GA repeats and can cause a high level antibody response which would be difficult to maintain with regular intravenous injection of monoclonal antibodies.
Although the distribution of antibodies across the blood-brain barrier is limiting, antibody engineering could, however, increase antibody delivery.
The safety profile of lifelong administration of highly immunogenic carriers should be studied before general application. Researchers have not noticed any side effects such as T-cell infiltration or other signs of meningoencephalitis, but unfortunately, experiments in mice cannot sufficiently predict the T-cell response in humans.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.