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.