Kate and Zoe will be presenting the following papers:
Koblan LW, et al. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice. Nature. 2021 Jan 6. doi: 10.1038/s41586-020-03086-7. Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders. Rabbani B, et al, J Hum Genet. 2012 Oct;57(10):621-32. doi: 10.1038/jhg.2012.91. Epub 2012 Jul 26. Review. PMID: 22832387 Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research. Wangler MF, Y et al., Genetics. 2017 Sep;207(1):9-27. doi: 10.1534/genetics.117.203067. Review. Progeria video: https://www.youtube.com/watch?v=GO306dK8m8c Please post questions for your classmates no later than NOON on Feb 1st to maintain your 5pts.Be prepared to ask this question or any question in class for another 5pts.
17 Comments
1/27/2024 02:46:29 pm
In the article "In Vivo Base Editing Rescues Hutchinson-Gilford Progeria Syndrome in Mice", the authors performed off-target DNA and RNA editing analysis to investigate the efficiency of their ABE editing in patient-derived cell lines. What is the difference between those two analysis in terms of their purpose, and how do those two analysis together contribute to the result ( should they always be consistent?)?
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Maggie Chrostowski
1/27/2024 06:26:56 pm
What would happen if both P3 and P14 mice were injected with the same amount of viral genomes?
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Rohan Babaria
1/28/2024 04:05:13 pm
In the article "In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice" They mention an outsized impact of edited cells in rescuing progeria mice from disease. We see this with a reduction of 31% reduction of progerin levels despite only .06 - 7.6% DNA correction. The study states that this may be possibly due to translation being more active in cells with the edit, however I was wondering if there were any other possible reasons (such as extracellular or gene-gene interaction effects) that may contribute to this occurrence.
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1/30/2024 11:10:48 am
In "Koblan LW, et al. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice." they describe a a gene therapy that is able to rescue a mouse model of progeria back to an undiseased state. Can you please explain further the AAV delivery system? What cell types are being edited? Was the gene therapy systemic or was the therapy designed to target a specific cell type?I am skeptical that they were able to edit a majority of the cells in the mouses body which is why clarification on the gene therapy target would be helpful.
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Sara Fritz
1/30/2024 12:50:26 pm
For the article "In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice" we see that there are a few different methods surrounding injection sites and timing. What do you think the benefit of doing injections at P3 versus P14 would be? What could this mean for clinical applications (or clinical trials)? Additionally there are different sites of injection, what do you think the reasoning is here for these sites (retro-orbital versus intraperitoneal)?
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Rebecca Wright
1/30/2024 09:58:35 pm
The discussion section of the article "In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice" mentions that the use of ABE editors to treat progeria shows promise for clinical applications. Do you know if any clinical trials have been planned or even started to investigate using this method to treat progeria in humans?
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Joely Swanson
1/31/2024 02:33:16 pm
In the article "In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice", it mentions that edited cells may contribute disproportionately to the health of tissues. Is the due to cells become more translationally active after editing or do you think that cells with higher translational activity are more likely to be edited?
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Brooke Fuerstenau
1/31/2024 05:32:52 pm
In the article "Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research," they talk a lot about diagnostic odyssey and the length of time it takes for most people to reach a correct diagnosis for a genetic disorder. How would you explain to others how model organisms have played a role in decreasing this diagnostic odyssey?
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Julia Carey
1/31/2024 05:53:42 pm
Did the delivery of the AAV9 encoding ABE and sgRNA in the in vivo model rescue the visible phenotypes, such as hair loss and musculoskeletal abnormalities, of the mice?
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Michelle Conte
1/31/2024 09:18:14 pm
How did the intraperitoneal injections compare to the retro-orbital injections of the P14 mice? Did the IP injections still yield a significant result? What were the IP injection phenotypic outcomes?
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Samuel Kivi
1/31/2024 09:55:58 pm
In the article "Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research", the researchers suggest that the study of human genetic diseases through model organisms could lead to new understandings of how genetic diseases could affect these organisms differently from humans. Could a reverse of this method (where a particular Mendelian genetic disease is discovered in a model organism, but if the same genetic mutation is discovered in a human, it's shown to have little/no affect on the human's phenotype) be a novel way of studying model organisms?
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2/1/2024 07:27:13 am
In the article "In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice", the authors posed a graph about ABE correction of progeria mutated gene (Fig 1.c). For both HGADFN167 and HGADFN188 gene expression graph, even the expression progerin cells decrease after ABEs treatment, the expressions for LMNA dramatically increase from 10 days to 20 days with small reduction of progeria cells comparatively. Would that indicate that the ABE is still not fully controllable and not efficiently for long term treatment.
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Dianna Xie
2/1/2024 08:54:20 am
In the article “In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice”, they mentioned that they extend the lifespan of progeria mice by performing allele correction using ABE, do you think allele correction can cause other diseases to the mice?
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perla larios
2/1/2024 09:34:34 am
In regards the "In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice" if the mutation came with a enlogated telomeres with a larger width would it be able to balance the mutation from the syndrome ?
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Muhammad Dar
2/1/2024 10:45:37 am
The authors of "In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice" describe the success of ABE base editors in treating Hutchinson-Gilford progeria syndrome. Beyond progeria, what other genetic diseases do you think could potentially benefit from ABE-based treatments? Can you discuss any ongoing research in this area? Also, how do you think this study contributes to the overall field of gene therapy and the future of personalized medicine for genetic disorders?
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Praneeth Venigalla
2/1/2024 11:25:53 am
In Koblan et al.'s study, in vivo base editing showed promise for treating Hutchinson-Gilford Progeria Syndrome in mice by directly correcting a genetic mutation. Given the significance of precise genetic mutations in Mendelian disorders as discussed by Rabbani et al., and the utility of model organisms in therapeutic research highlighted by Wangler et al., how do you compare the potential of in vivo base editing versus traditional gene therapy approaches in addressing not just single-gene disorders but also complex genetic diseases?
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Madeline Blum
2/1/2024 12:00:30 pm
In Kobal LW et al, it had been observed that five of the P14 mice had liver tumors associated with the AAV9 treatment, as has previously been observed in mice. This was found to be unrelated to the base editing technique in question. Why do you suppose this issue was only found in P14 mice? Is it associated with the higher AAV9 dose? Despite higher effects on rescuing vascular smooth muscle, should P13 be a prioritized in effort to reduce this possibility in mice?
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