Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10-15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

Fig. 1. ALS pathophysiology, genetic causes and risk factors.

Advances in large-scale genomic analysis have uncovered a variety of causative genes and risk factors for amyotrophic lateral sclerosis (ALS). These gene variants map onto key pathogenic mechanisms relevant to all motor neuron cellular compartments as well as neighbouring cells such as glia and interneurons. In this way, these mechanisms are genetically validated, enabling a greater confidence in their targeting for therapeutic benefit. Some of these mechanisms have emerged only in recent years due to new genetic information, including gene changes highlighting dysregulation of RNA processing and metabolism. There is significant overlap of some genes with those found in closely related disorders such as frontotemporal dementia (for example, C9orf72, CHCHD10, SQSTM1, TBK1, CCNF, FUS, TARDBP, OPTN, UBQLN2, TUBA4A, ATAXN2, VCP and CHMP2B). This suggests a closer relationship to broader neurodegenerative disorders, and indeed many of the pathways depicted are relevant in, for example, Alzheimer disease. ER, endoplasmic reticulum. For a complete list of the ALS loci, genes and associated proteins, see Supplementary Table 2.

Fig. 2. The major ALS pathophysiological targets currently being pursued.

We have identified over 40 active clinical programmes (Table 2) and over 50 late-stage preclinical programmes (Table 3) and show here how these efforts map onto the pathophysiological landscape of amyotrophic lateral sclerosis (ALS). Among clinical programmes, some trends emerge. Neuroinflammation is the best represented therapeutic target covered by a variety of approaches, with the complement system representing a particular target of interest. Genetic therapies using antisense oligonucleotide (ASO) approaches also dominate the clinical space targeting specific ALS genes, although Ataxin2 modifiers may be more broadly applicable in relation to TDP-43 proteinopathy. Genetic therapies are also prominent in preclinical efforts. Other notable areas include proteostasis and cell therapies. Considering the most up to date understanding of pathomechanisms and genetics, several areas are poised for further exploration in sporadic ALS more broadly, including RNA metabolism and axonopathy. AAV, adeno‐associated virus; mAb, monoclonal antibody; MSC, mesenchymal stem cell; TUDCA, tauroursodeoxycholic acid.

Fig. 3. A rational and enhanced preclinical efficacy screening cascade for ALS.

In terms of efficacy assessment and increasing confidence in translation from the preclinical to the clinical arena, an enhanced approach would take advantage of the latest developments in preclinical disease modelling in rodents and non-rodent in vivo systems, as well as patient-derived cellular models. A standard in vitro cascade is shown for a target-based approach, which is subsequently confirmed at an early stage in a relevant patient-derived phenotypic model. Such models can be used as orthogonal screens through a development programme to ensure that efficacy against a relevant disease phenotype is maintained. At later stages in vivo mammalian models can be used as purely mechanistic pharmacokinetic/pharmacodynamic systems to ensure that therapeutic approaches have the required drug metabolism and pharmacokinetics, potency and specificity in vivo. Subsequently, confidence in clinical translation can be obtained in either more extensive screening in patient-derived model systems or complex disease models. Ideally several approaches should be pursued. These complex models with behavioural readouts of motor function would incorporate ‘translational’ biomarkers that have the potential to predict likely clinical benefit, such as measurements of compound muscle action potential (CMAP) and neurofilament light. ALS, amyotrophic lateral sclerosis; CSF, cerebrospinal fluid; iPSC, induced pluripotent stem cell; MN, motor neuron; PD, pharmacodynamic; PK, pharmacokinetic.