From animal models to human disease: a genetic approach for personalized medicine in ALS

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

The challenges of developing a gene therapy for amyotrophic lateral sclerosis

“…Generally, the gene therapy strategy for sALS focuses on introducing neuroprotective agents like neurotrophic factors. The strategy for fALS focuses on addressing specific gene mutations [2,3]. On both fronts, preliminary research has shown progress, but successes are tempered by subsequent failures to scale up to translation.…”

“…C9orf72 and NEK1) [3,13]. However, one great difficulty is that the symptomology and histology of ALS are not necessarily recapitulated in these models, meaning refinements are necessary [3].…”

“…A critical translational gap is that small-animal and in vitro models do provide a space for proof-of-principle, but have not adequately paralleled human disease phenotypes [3,14]. The end result is that few therapies have reached a pre-clinical state and that none have reached the clinic.…”

Clinical and laboratory features of ALS

“…The SOD1 rodent model is the most common animal model of ALS. Different gene mutations have been used in the SOD1 mice model [96] . There are heterogeneous phenotypical manifestations in SOD1 models with different gene mutations.…”

“…There are heterogeneous phenotypical manifestations in SOD1 models with different gene mutations. These vary in rate of progression, time of symptom onset and pathological findings [96] .…”