Investigating a novel splice switching oligonucleotide treatment for Friedreich Ataxia in a transgenic frataxin mouse model
Location
Medical Education Building, LSUHSC-NO
Presentation Date
10-10-2019 10:00 AM
End Date
10-10-2019 12:00 PM
Description
Friedreich Ataxia (FRDA) is a severe disease caused by triplet repeat expansion of intron 1 in the frataxin (FXN) gene, leading to progressive ataxia, dysarthria, scoliosis, and hypertrophic cardiomyopathy. The disease occurs in 1 in 40,000 people, usually becoming symptomatic at age 10 and causing death by age 37. The length of the gene expansion is correlated with levels of FXN protein and disease severity. The triplet repeat expansion leads to loop formation and activation of the MutLγ mismatch repair complex that further expands the intron, leading to transcriptional repression of the frataxin protein and subsequent reduction of iron sulfur clusters in the mitochondria. Currently, there is no cure for FRDA, but several potential treatment therapies are in the process of development, focusing on either increasing the levels of FXN or reducing the oxidative stress which is a result of reduced iron-sulfur cluster biosynthesis. By targeting the mismatch repair mechanism responsible for the triplet repeat expansion of the FXN gene, we are developing a novel treatment for FRDA which slows down the expansion of the FXN gene. Using Intracerebroventricular (ICV) injections in a transgenic Friedreich Ataxia mouse model, I analyzed the efficacy of 2’MOE splice switching oligonucleotides (SSO) in the central nervous system designed to target the pre-mRNA for MLH3 of the mismatch repair complex, MutLγ, and splice out the endonuclease domain located in exon 6. This results in the inability of the repair complex to cleave the DNA and add nucleic acid bases, stopping expansion of the genome. To verify that our mouse model had genetic expansion in the tissues of interest, I analyzed various tissues in the transgenic frataxin mouse model to compare the rates of expansion. I saw considerable expansion in both the cerebral cortex and the cerebellum, which confirms that our mouse model will be appropriate to use for the ICV treatment. By targeting the mechanism involved in the repeat expansion, we can prevent the progression of the fatal disease. This could provide relief to the people suffering from this genetic disease and could also be a treatment applicable to other repeat expansion disorders, such as Huntington’s Disease, that use the same mismatch repair mechanism to expand. By slowing down the expansion of the FXN gene, we can slow down progression of the disease in symptomatic people and possibly provide a treatment to screened children so that they may never become symptomatic.
Recommended Citation
Henderson, Ashley S., "Investigating a novel splice switching oligonucleotide treatment for Friedreich Ataxia in a transgenic frataxin mouse model" (2019). Medical Student Research Poster Symposium. 16.
https://digitalscholar.lsuhsc.edu/sommrd/2019/posters/16
Investigating a novel splice switching oligonucleotide treatment for Friedreich Ataxia in a transgenic frataxin mouse model
Medical Education Building, LSUHSC-NO
Friedreich Ataxia (FRDA) is a severe disease caused by triplet repeat expansion of intron 1 in the frataxin (FXN) gene, leading to progressive ataxia, dysarthria, scoliosis, and hypertrophic cardiomyopathy. The disease occurs in 1 in 40,000 people, usually becoming symptomatic at age 10 and causing death by age 37. The length of the gene expansion is correlated with levels of FXN protein and disease severity. The triplet repeat expansion leads to loop formation and activation of the MutLγ mismatch repair complex that further expands the intron, leading to transcriptional repression of the frataxin protein and subsequent reduction of iron sulfur clusters in the mitochondria. Currently, there is no cure for FRDA, but several potential treatment therapies are in the process of development, focusing on either increasing the levels of FXN or reducing the oxidative stress which is a result of reduced iron-sulfur cluster biosynthesis. By targeting the mismatch repair mechanism responsible for the triplet repeat expansion of the FXN gene, we are developing a novel treatment for FRDA which slows down the expansion of the FXN gene. Using Intracerebroventricular (ICV) injections in a transgenic Friedreich Ataxia mouse model, I analyzed the efficacy of 2’MOE splice switching oligonucleotides (SSO) in the central nervous system designed to target the pre-mRNA for MLH3 of the mismatch repair complex, MutLγ, and splice out the endonuclease domain located in exon 6. This results in the inability of the repair complex to cleave the DNA and add nucleic acid bases, stopping expansion of the genome. To verify that our mouse model had genetic expansion in the tissues of interest, I analyzed various tissues in the transgenic frataxin mouse model to compare the rates of expansion. I saw considerable expansion in both the cerebral cortex and the cerebellum, which confirms that our mouse model will be appropriate to use for the ICV treatment. By targeting the mechanism involved in the repeat expansion, we can prevent the progression of the fatal disease. This could provide relief to the people suffering from this genetic disease and could also be a treatment applicable to other repeat expansion disorders, such as Huntington’s Disease, that use the same mismatch repair mechanism to expand. By slowing down the expansion of the FXN gene, we can slow down progression of the disease in symptomatic people and possibly provide a treatment to screened children so that they may never become symptomatic.
Comments
Mentor: Dr. Edward Grabczyk (Associate Professor of Genetics)