Fig. 4

Gene therapy mechanism of action. Schematic representation of possible gene therapy approaches in ALS treatment. All of these approaches can be effective by intra-thecal, intracerebroventricular or peripheral injection of AAV or lentivirus targeting motor neurons or glial cells. a Antisense olinucleotide (ASO) are short synthetic oligonucleotides (15-25 nucleotides) which bind to targeted mRNA. ASO reduces the expression of a specific protein by two main mechanisms. ASO induces the mRNA degradation by endogenous RNase H or blocks the mRNA translation. This is a potential therapeutic avenue in ALS by reducing the protein level of TDP-43, SOD1 of FUS protein level or by targeting of C9orf72 RNA foci. b SiRNAs are double-stranded RNAs which operated through RNA interference pathway. After strand unwinding, one siRNA strand binds argonaute proteins as part of the RNA-induced silencing complex (RISC) and is recruited to a target mRNA which is then cleaved. c Antibodies are another potential therapeutics avenue in ALS [111]. Antibodies can target misfolded proteins and reduce the amount of toxic aggregates. It is suggested that they can reduces the disease propagation between cells. They can also be exploited to block the pathological interaction between proteins by binding to the specific interaction sites. d Gene delivery is another potential therapeutic avenue for loss-of-function mutations. Virus can provide a functional replacement of a missing gene by mRNA or cDNA delivery. This approach was particularly tested in spinal muscular atrophy and revealed great outcomes but is not yet extensively tested in ALS [231]