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

Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N - Acta Neuropathol Commun (2016)

Bottom Line: 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.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.Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

Gene therapy mechanism of action. Schematic representation of possible gene therapy approaches in ALS treatment. All of these approaches can be effective by intra-thecal, intracerebroventricular or peripheral injection of AAV or lentivirus targeting motor neurons or glial cells. a Antisense olinucleotide (ASO) are short synthetic oligonucleotides (15-25 nucleotides) which bind to targeted mRNA. ASO reduces the expression of a specific protein by two main mechanisms. ASO induces the mRNA degradation by endogenous RNase H or blocks the mRNA translation. This is a potential therapeutic avenue in ALS by reducing the protein level of TDP-43, SOD1 of FUS protein level or by targeting of C9orf72 RNA foci. b SiRNAs are double-stranded RNAs which operated through RNA interference pathway. After strand unwinding, one siRNA strand binds argonaute proteins as part of the RNA-induced silencing complex (RISC) and is recruited to a target mRNA which is then cleaved. c Antibodies are another potential therapeutics avenue in ALS [111]. Antibodies can target misfolded proteins and reduce the amount of toxic aggregates. It is suggested that they can reduces the disease propagation between cells. They can also be exploited to block the pathological interaction between proteins by binding to the specific interaction sites. d Gene delivery is another potential therapeutic avenue for loss-of-function mutations. Virus can provide a functional replacement of a missing gene by mRNA or cDNA delivery. This approach was particularly tested in spinal muscular atrophy and revealed great outcomes but is not yet extensively tested in ALS [231]
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Fig4: Gene therapy mechanism of action. Schematic representation of possible gene therapy approaches in ALS treatment. All of these approaches can be effective by intra-thecal, intracerebroventricular or peripheral injection of AAV or lentivirus targeting motor neurons or glial cells. a Antisense olinucleotide (ASO) are short synthetic oligonucleotides (15-25 nucleotides) which bind to targeted mRNA. ASO reduces the expression of a specific protein by two main mechanisms. ASO induces the mRNA degradation by endogenous RNase H or blocks the mRNA translation. This is a potential therapeutic avenue in ALS by reducing the protein level of TDP-43, SOD1 of FUS protein level or by targeting of C9orf72 RNA foci. b SiRNAs are double-stranded RNAs which operated through RNA interference pathway. After strand unwinding, one siRNA strand binds argonaute proteins as part of the RNA-induced silencing complex (RISC) and is recruited to a target mRNA which is then cleaved. c Antibodies are another potential therapeutics avenue in ALS [111]. Antibodies can target misfolded proteins and reduce the amount of toxic aggregates. It is suggested that they can reduces the disease propagation between cells. They can also be exploited to block the pathological interaction between proteins by binding to the specific interaction sites. d Gene delivery is another potential therapeutic avenue for loss-of-function mutations. Virus can provide a functional replacement of a missing gene by mRNA or cDNA delivery. This approach was particularly tested in spinal muscular atrophy and revealed great outcomes but is not yet extensively tested in ALS [231]

Mentions: Personalized medicine approaches allow physicians to group together patients with similar characteristics. This could be performed with the use of biomarkers and over time with the same mutated gene. We have reviewed specific treatments which could be applied to sub-groups of patients with ALS. We consider that gene therapy has great potential for personalized medicine approaches, either by antisense oligonucleotide, small interference RNA or any other method such as antibodies targeting pathological proteins (Fig. 4). These techniques have already been tested and appear to be effective in SOD1, TDP-43, C9ORF72 and FUS animal models [111–115, 157, 179, 212]. We are optimistic that the use of gene therapy will growth in clinical trials in the next few years. Promising technologies for delivering genes have been suggested and revealed many procedures for safely targeting central nervous system. Lentiviral or AAV injections or peripherally injected exosomes which specifically target neurons are within these auspicious avenues.Fig. 4


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

Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N - Acta Neuropathol Commun (2016)

Gene therapy mechanism of action. Schematic representation of possible gene therapy approaches in ALS treatment. All of these approaches can be effective by intra-thecal, intracerebroventricular or peripheral injection of AAV or lentivirus targeting motor neurons or glial cells. a Antisense olinucleotide (ASO) are short synthetic oligonucleotides (15-25 nucleotides) which bind to targeted mRNA. ASO reduces the expression of a specific protein by two main mechanisms. ASO induces the mRNA degradation by endogenous RNase H or blocks the mRNA translation. This is a potential therapeutic avenue in ALS by reducing the protein level of TDP-43, SOD1 of FUS protein level or by targeting of C9orf72 RNA foci. b SiRNAs are double-stranded RNAs which operated through RNA interference pathway. After strand unwinding, one siRNA strand binds argonaute proteins as part of the RNA-induced silencing complex (RISC) and is recruited to a target mRNA which is then cleaved. c Antibodies are another potential therapeutics avenue in ALS [111]. Antibodies can target misfolded proteins and reduce the amount of toxic aggregates. It is suggested that they can reduces the disease propagation between cells. They can also be exploited to block the pathological interaction between proteins by binding to the specific interaction sites. d Gene delivery is another potential therapeutic avenue for loss-of-function mutations. Virus can provide a functional replacement of a missing gene by mRNA or cDNA delivery. This approach was particularly tested in spinal muscular atrophy and revealed great outcomes but is not yet extensively tested in ALS [231]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4940869&req=5

Fig4: Gene therapy mechanism of action. Schematic representation of possible gene therapy approaches in ALS treatment. All of these approaches can be effective by intra-thecal, intracerebroventricular or peripheral injection of AAV or lentivirus targeting motor neurons or glial cells. a Antisense olinucleotide (ASO) are short synthetic oligonucleotides (15-25 nucleotides) which bind to targeted mRNA. ASO reduces the expression of a specific protein by two main mechanisms. ASO induces the mRNA degradation by endogenous RNase H or blocks the mRNA translation. This is a potential therapeutic avenue in ALS by reducing the protein level of TDP-43, SOD1 of FUS protein level or by targeting of C9orf72 RNA foci. b SiRNAs are double-stranded RNAs which operated through RNA interference pathway. After strand unwinding, one siRNA strand binds argonaute proteins as part of the RNA-induced silencing complex (RISC) and is recruited to a target mRNA which is then cleaved. c Antibodies are another potential therapeutics avenue in ALS [111]. Antibodies can target misfolded proteins and reduce the amount of toxic aggregates. It is suggested that they can reduces the disease propagation between cells. They can also be exploited to block the pathological interaction between proteins by binding to the specific interaction sites. d Gene delivery is another potential therapeutic avenue for loss-of-function mutations. Virus can provide a functional replacement of a missing gene by mRNA or cDNA delivery. This approach was particularly tested in spinal muscular atrophy and revealed great outcomes but is not yet extensively tested in ALS [231]
Mentions: Personalized medicine approaches allow physicians to group together patients with similar characteristics. This could be performed with the use of biomarkers and over time with the same mutated gene. We have reviewed specific treatments which could be applied to sub-groups of patients with ALS. We consider that gene therapy has great potential for personalized medicine approaches, either by antisense oligonucleotide, small interference RNA or any other method such as antibodies targeting pathological proteins (Fig. 4). These techniques have already been tested and appear to be effective in SOD1, TDP-43, C9ORF72 and FUS animal models [111–115, 157, 179, 212]. We are optimistic that the use of gene therapy will growth in clinical trials in the next few years. Promising technologies for delivering genes have been suggested and revealed many procedures for safely targeting central nervous system. Lentiviral or AAV injections or peripherally injected exosomes which specifically target neurons are within these auspicious avenues.Fig. 4

Bottom Line: 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.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.Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus