Motor neuron diseases (MNDs) are a family of neurodegenerative disorders that selectively affect upper and/or lower MNs, which control voluntary movements. Although incurable until a few years ago, with the new advancements in gene therapy, patients affected by mutations in SOD1, causing ALS, or in SMN, causing SMA, are nowadays treated with significant improvements. In this symposium we will discuss ongoing clinical trials in ALS, novel therapeutic avenues in SMA, and promising gene therapy approaches in spinal and bulbar muscular atrophy (SBMA), another MND caused by the expression of polyglutamine-expanded androgen receptor.
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11:30am - 12:15pmGenetic forms of ALS, from the clinics to the therapy
Adriano Chiò
University of Turin, Italy
Amyotrophic lateral sclerosis (ALS) is considered a multifactorial disorder caused by an interaction between genetics and the environment. While relatively little is known about the environmental contributions to ALS, pathogenic variants in more than forty genes have been linked to the disease, the most common being C9orf72, SOD1, TARDBP and FUS. The genetic contribution to ALS is estimated to be between 40 and 60%. Extensive genetic studies have identified pathogenic variants in about 25% of all cases, independently from the presence of a family history for the disease. Genetic epidemiology revealed that the frequency of major genes in population with different ethnic ancestry is quite different, underling the necessity of perform studies in population outside Caucasians and Asians.
In addition to disease-causing genes, several other genes have been reported to be modifiers of ALS phenotype, especially patients’ survival. Among these, the most relevant are UNC13A (rs12608932 variant), CAMTA1 (rs2412208 variant), ATXN2 (intermediate polyQ repeats). These disease-modifying variants are now considered for specific clinical trials.
The discovery of ALS-related genes and their pathogenetic mechanisms allows to move to innovative therapeutic approaches. Several trials using antisense oligonucleotides (ASO) have been or are currently performed. A phase 3 trial based on Tofersen, an ASO specific for SOD1 mRNA, gave positive results, in particular in the open label extension phase, causing the registration of the drug by FDA. A promising study is also ongoing on an OLE specific for FUS (Jacifusen) with interesting preliminary results. Another study on an ASO against C9orf72 was stopped because of lack of efficacy. A different approach, i.e., SOD1 Suppression with Adeno-Associated Virus and MicroRNA has been studied in a phase 1. Also, approaches based on DNA genome editing with methods, such as CRISPR/CRISPR-associated protein (CRISPR/Cas) are under study in preclinical models.
12:15pm - 12:35pmEthipathogenesis and new therapeutic targets for SMA
Linda Ottoboni
University of Milan, Italy
Spinal Muscular Atrophy (SMA) is a debilitating genetic neuromuscular disorder characterized by progressive muscle weakness and atrophy, resulting from the loss of specialized motor neurons in the spinal cord. The presentation will provide an overview of the ethipathogenesis of SMA and of consolidated therapeutic strategies with insights on new targets that hold promise for the treatment of this devastating condition.
The pathogenesis of SMA is primarily attributed to the homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene, leading to reduced levels of the SMN protein whose deficiency disrupts various cellular processes, including RNA metabolism, protein synthesis, and mitochondrial functions, ultimately resulting, as major outcome, in motor neuron degeneration.
Current therapeutic targets focus on the modulation of SMN2, the paralogous gene, leveraging its alternative splicing during pre-mRNA processing to enhance SMN protein production.
Additionally, emerging research has identified various molecular pathways implicated in SMA and offering new therapeutic avenues, which have been tackled through small molecules or gene therapies, with primary focus on motoneuron preservation.
Alternative strategies are targeting neuromuscular junctions or muscles, with combination therapies as novel strategies
Our lab is currently exploring the importance of STMN2 in the context of SMA in a severe mouse model and exploiting disease specific spinal organoids exposed to therapeutic intervention to better profile the presymptomatic condition and alternative therapeutic targets which might,offer viable complementary treatments also for late diagnosed patients.
12:35pm - 12:50pmModulation of mutant TDP-43 within astrocytes ameliorates disease progression in a mouse model of Amyotrophic Lateral Sclerosis
Anna Micol Barbieri1, Alice Migazzi1, Laura Pasetto2, Sergio Robbiati1, Valentina Bonetto2, Manuela Basso1,2
1Università degli Studi di Trento, Italy; 2Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
Amyotrophic Lateral Sclerosis (ALS) is a non-cell autonomous neurodegenerative disease that affects neuronal cells in the brain and spinal cord. Glial cells play a key role in ALS pathogenesis and contribute to the progression of the disease, but further research is needed to fully understand this complex interplay.
In recent years, our lab has been investigating the role of astrocyte-to-neuron miscommunication in a mouse model of ALS. To further understand the contribution of astrocytes, we selectively removed the mutated TDP-43 Q331K from astrocytes in our mouse model using an inducible Cre-loxP system under the control of the astrocyte-specific GLAST promoter. Eliminating the mutated TDP-43 Q331K from astrocytes was sufficient to improve cognitive and motor function compared to TDP-43 Q331K mice. Cohorts were tested for Three-Chambers Social Task, Elevated Plus Maze, accelerated Rotarod, and Grip Strength at different age stages. Decreased axonal damage can be noticed also by neurofilament light chain (NfL) quantification from blood samples at early symptomatic stages (6 months). To validate the effective removal of the TDP-43 Q331K protein only from astrocyte populations and not neuronal ones, we performed an immunohistochemistry assay.
As previously demonstrated also in SOD1 mutant mice, another ALS-associated gene, glial cells have a role in disease progression. To further investigate this contribution, we are performing RNA-sequencing at different time points on astrocytes and oligodendrocytes derived from the brain and spinal cord of our model, using Miltenyi Isolation Kits. This sequencing will allow us to identify new markers for disease progression and possibly find potential therapeutic targets that could halt or slow down the progression of the disease.
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