Amyotrophic Lateral Sclerosis: treating the circuit behind the disease

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The incurable disease Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons (MNs), which are the nerve cells directly controlling movements since they connect to the muscles in the periphery of the body. So, MNs can be considered the output of the brain; however, they are activated by a complex circuit of nerve cells found in the spinal cord that decodes the information coming from the brain and activates the MNs in a synchronised manner. These decoding neurons (also called interneurons) can either excite or inhibit the MNs depending on which part of the circuit needs to be engaged to perform the desired movement. We recently discovered that, in a mouse model of ALS, a group of inhibitory interneurons loses its connection to the MNs early in disease, and cannot activate them properly anymore. These changes in connectivity can contribute to MNs dysregulation and degeneration. We also saw that loss of connectivity led to symptoms resembling the ones observed in patients, which included changes in the stride and speed of locomotion (Allodi et al 2021, Nature Communication). In a new study (Mora et al 2022), we used an approach which uses viral infection to deliver genes as therapy, called gene therapy. We delivered a gene that naturally stimulates connections between nerve cells, and we increased the levels of this gene specifically in the inhibitory interneurons. This approach allowed us to stabilise the connectivity between the inhibitory interneurons and the MNs, and as a consequence we increased MN survival and ameliorated ALS symptoms in mice. However, to date, our results are obtained from a mouse model carrying the SOD1 mutation known to cause familial ALS, which accounts only for the 2% of the ALS cases. For this reason, we are now planning to broaden our investigations also to other ALS-causing genetic mutations and to clarify if the loss of connectivity between inhibitory interneurons and MNs is a common event in ALS pathology. If this happen to be the case, our new gene therapy could be apply to a wider number of ALS cases in the future. In this project, we will investigate if the inhibitory interneurons are affected in two other mouse models carrying the TDP-43 and the FUS mutations, utilising an approach that allows us to visualise the connections between interneurons and MNs, and to quantify them. This approach was previously established in the lab (Allodi et al 2021, Nature Communication) and will help us identifying the potential loss of connectivity. Secondly, we will investigate if inhibitory interneurons are also affected in sporadic ALS. Thanks to our collaboration with the Bjspebjerg Brain Bank in Denmark, we can analyse post-mortem tissue from 21 donors which were diagnosed with sporadic ALS. Here, inhibitory interneurons will be quantified to elucidate their potential degeneration in sporadic ALS cases. The inhibitory interneurons will be counted instead of their connections, because the level of degeneration in the human post-mortem tissue is high and we expect a lot of the connectivity to be lost. Finally, we will generate an improved gene therapy to deliver the gene that naturally stimulates connectivity in humans. Despite the promising results, our current approach (Mora et al 2022) has translational limitations because uses a genetic strategy not applicable in humans. However, the inhibitory interneurons can be targeted using a DNA sequence that is specific (like a barcode) and conserved in mouse, chimps, and humans. This sequence can be used as an enhancer. The enhancer will target only the specific inhibitory interneurons and force the expression of our treatment in the cells. Importantly, this new gene therapy can be administered by intravenous injection, so it does not require invasive treatments. We hope that this strategy will slow down inhibitory interneurons from losing their connections and MNs from degeneration.