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Acta Neuropathol Commun. 2016 Jul 11;4(1):70. doi: 10.1186/s40478-016-0340-5.

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

Author information

1
Department of Psychiatry and Neuroscience, Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. vincent.picher-martel.1@ulaval.ca.
2
Departments of Pediatrics and Genetics, Stanford University, 269 Campus Drive, CCSR 2110, Stanford, CA, 94305-5164, USA.
3
Division of Anatomic Pathology and Neuropathology, Department of Medical Biology, CHU de Québec, Hôpital de l'Enfant-Jésus, 1401, 18th street, Québec, QC, Canada, G1J 1Z4.
4
Department of Psychiatry and Neuroscience, Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.
5
Axe Neurosciences & The Department of Medicine, Faculty of Medicine, CHU de Québec, Laval University, 1401, 18th street, Québec, QC, G1J 1Z4, Canada. nicolas.dupre.cha@ssss.gouv.qc.ca.

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.

KEYWORDS:

Amyotrophic lateral sclerosis (ALS); Animal models; Biomarkers; Frontotemporal dementia (FTD); Gene therapy; Mouse; Personalized medicine

PMID:
27400686
PMCID:
PMC4940869
DOI:
10.1186/s40478-016-0340-5
[Indexed for MEDLINE]
Free PMC Article

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