Intravacc, a contract development and manufacturing organization (CDMO) of preventive and therapeutic vaccines and the German Center for Neurogenerative Diseases (DZNE), have been awarded a funding of € 2.5 million from the European Union (EIC Transition Grant) to further develop a prototype C9orf72 ALS vaccine.

Mutations in C9orf72 gene causes excessive repeats of six nucleotides GGGGCC. These extra repeats lead to the production of abnormal proteins, called dipeptide repeat proteins (DPR). Moreover, excessive GGGGCC repeats in the C9orf72 gene also are one of the most common causes of frontotemporal dementia (FTD).

Researchers from the German Center for Neurogenerative Diseases hypothesized that using a vaccine to induce the production of such antibodies by the body’s immune system could be a potential therapy for ALS and FTD linked to C9orf72 gene mutations.

This is a concept close to ASO, but it would make the body continuously targeting those repeats, while ASO work only for a short time after administration.

In recent years, there has been increasing interest in the use of monoclonal antibodies to treat neurodegenerative disorders, with the goal of targeting misfolded intra- or extra-cellular proteins, such as amyloid beta peptide, tau, or alpha-synuclein.

Very recently, the U.S. FDA has approved Aducanumab, a recombinant monoclonal antibody against amyloid beta plaques, for the treatment of Alzheimer's disease patients.

Antibodies show a considerable number of advantages when used for therapeutic purposes. They possess a long half-life, and, due to their nature, they can efficiently target proteins in their physiological state, after post-translational modifications or in a misfolded conformation, with high specificity and affinity.

Yet there were many pre-clinical studies involving antibodies against SOD1 or TDP-43 without much success. In 2019 a study had more success with C9orf72.

Antibodies are big molecules and might pose difficulties in penetrating the CNS due to the natural defense structure of the blood-brain barrier (BBB). The use of single chain antibodies could overcome this issue since they are smaller in size and possess higher cellular penetration capacity.

Antibodies treatment starting at the pre-symptomatic stage often proves less effective when delivered at the symptomatic stage, corroborating the need to evaluate therapeutic efficacy when the pathology has already manifested itself. As sporadic ALS patients are diagnosed only years after the beginning of their symptoms, it is unclear how such therapies could be effective.

What strikes me, is that despite the high number of studies on ALS, all the attempts to make therapies seem to explore only rather improbable paths.

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turning off C9orf72-repeat toxicity by downregulating PAF1C.

- Posted by admin in English

Familial ALS represents a small percentage of all ALS cases and C9ORF72 is the most common mutated gene in familial ALS.

An interesting study identifies PAF1C, as a transcription complex needed to read the C9ORF72 gene expansion RNA in flies and yeast. PAF1C components were upregulated in brain samples from people with C9ORF72-FTD, and bound to the C9ORF72 promoter. The role of PAF1C in expression of the expanded repeats suggests its human homolog may be a target for mitigating C9ORF72 toxicity. It used is about fruit flies, yeast and human tissues. Indeed fruit flies and yeast even more stranger to human CNS than genetically engineered mice. But it is this study that stroked my interest, because they found a link with human FTD where C9 is implicated.

Lindsey Goodman suggests that a potential route to turning off C9orf72-repeat toxicity may be to avert its transcription in the first place.

Using a genetic screen in fruit flies, the scientists sought genes that temper the toxicity of the GGGGCC hexanucleotide repeat that is found in C9orf72 and that lead to the transcription of the C9ORF72-encoded poly(GR) dipeptide. enter image description here

They were interested in several components of the PAF1C RNA polymerase III complex, which is especially good at transcribing GC-rich DNA. They identified several PAF1C components as modifiers of C9orf72-associated disease.

Transgenic downregulation of PAF1C components disrupted the transcription of G4C2 RNA in both Drosophila and Saccharomyces cerevisiae and resulted in reduced toxicity in Drosophila. in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2) 30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+ -derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In human C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.

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