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Can we treat chromosomal abnormalities?

Image credit: Wessex Reg. Genetics Centre. Attribution 4.0 International (CC BY 4.0)

Jamila Jan 11, 2021

[1]New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services. Understanding genetics: a New York, mid-Atlantic guide for patients and health professionals. Lulu. com, 2009.

[2]Wolff, Sheldon. “Chromosome aberrations.” Radiation Protection and Recovery (A. Hollaender, ed.) 7 (2013): 157-174.

[3]Kazemi, Mohammad, Mansoor Salehi, and Majid Kheirollahi. "Down syndrome: current status, challenges and future perspectives." International journal of molecular and cellular medicine 5.3 (2016): 125.

Creative contributions

Using XIST controlled dosage compensation to rectify trisomy

Subash Chapagain
Subash Chapagain Jan 13, 2021

[1]Jiang, J., Jing, Y., Cost, G. et al. Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013). https://doi.org/10.1038/nature12394

[2]Disteche, C. M. (2012). Dosage Compensation of the Sex Chromosomes. Annual Review of Genetics, 46(1), 537–560. https://doi.org/10.1146/annurev-genet-110711-155454

[3]Andrew J. Sharp, Hugh T. Spotswood, David O. Robinson, Bryan M. Turner, Patricia A. Jacobs, Molecular and cytogenetic analysis of the spreading of X inactivation in X;autosome translocations, Human Molecular Genetics, Volume 11, Issue 25, 1 December 2002, Pages 3145–3156, https://doi.org/10.1093/hmg/11.25.3145

[4]Fabio Savarese, Katja Flahndorfer, Rudolf Jaenisch, Meinrad Busslinger, Anton Wutz Hematopoietic Precursor Cells Transiently Reestablish Permissiveness for XInactivation Molecular and Cellular Biology Sep 2006, 26 (19) 7167-7177; DOI: 10.1128/MCB.00810-06

[5]Berletch, J.B., Yang, F., Xu, J. et al. Genes that escape from X inactivation. Hum Genet 130, 237–245 (2011). https://doi.org/10.1007/s00439-011-1011-z

[6]Engreitz, J. M., Pandya-Jones, A., McDonel, P., Shishkin, A., Sirokman, K., Surka, C., Kadri, S., Xing, J., Goren, A., Lander, E. S., Plath, K., & Guttman, M. (2013). The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome. Science, 341(6147), 1237973. https://doi.org/10.1126/science.1237973

Jamila a month ago
Hello Subash Chapagain, thanks for the great contribution.

The XIST system sounds fascinating. So, from what I’ve read this is what I’ve gathered (pls correct me if I’m wrong): XIST is basically a gene that researchers insert into chromosomes to silence them. When the XIST system is transcribed, it produces a long non-coding RNA, which activates chromatin modifications that silence transcription of the chromosome. Therefore, you get a silenced chromosome, which should, in theory, alleviate trisomy-associated effects.

Thoughts for the future:
- If XIST worked in Down syndrome patients, I wonder if regular treatments would be required or just a one-off?
-I wonder how 1/3 of chromosomes at chromosome 21 would be silenced with XIST system, i.e. how would the XIST system specifically target the extra chromosome?

Subash Chapagain
Subash Chapagaina month ago
Hi Jamila, what you have asked as an afterthought seems really intriguing. To be honest, this had not crossed my mind when I posted the contribution. In my knowledge, the treatment is supposed to be one-off, given that the engineered chromosome is expected to be replicated even with subsequent replicative cycles. However, this is exactly where the researchers were sceptic because in some cell lines the silencing was lost after a few cycles of cell division.

The XIST system is engineered under an inducible promoter which in this case has been induced with Doxycycline. I am not exactly sure how they attained it, but I think if the XIST is expressed in one chromosome, the remaining ones don't express the gene. I would have to take a deeper look into the literature to see if that is correct, and if not how it is attained.
Jamila a month ago
Subash Chapagain, thanks for answering my question. That's interesting; I wonder what caused some of the cell lines to lose the silencing after a number of cell divisions. I guess this means that researchers still need to figure out whether it would be a one-off treatment or continuous treatment.

I'm not sure whether the XIST system being a one-off treatment would have superior therapeutic benefits or not, but it would definitely be more convenient for the patient to have a one-off treatment.

Using CRISPR to treat trisomies

Jamila Jan 12, 2021

[1]Zuo, Erwei, et al. "CRISPR/Cas9-mediated targeted chromosome elimination." Genome biology 18.1 (2017): 224.

Antonio Carusillo
Antonio Carusilloa month ago
You highlighted exactly my point: do they disclose/ explain how to target only 1/3 chromosome 21? Were the targets based on allelic specific SNPs? Meaning that there are certain repetitions which are only found in one of the 3 chromosomes 21? Allelic specific CRISPR editing has been reported, also recently ( https://www.sciencedirect.com/science/article/abs/pii/S1525001620302367 ).

Also, another point would be to understand WHEN to perform the editing to be effective, Down Syndrom affects development with cognitive impairment. So, theoretically, in such cases the earlier you act the better it is. This to prevent the accumulation of damages due to the condition.
On the other hand, when we speak about targeting a condition which does not affect only a certain cell type and that affects the whole organism at once, you would like to target as many cells as possible.
Again this is a reason to target an organism at the earliest time point, cause simply put there are fewer cells to edit.
Even if, embryo editing would be the way to go, we are all aware that this is option is not legal in particular after the "CCR5 babies" scandal ( https://www.sciencemag.org/news/2019/08/did-crispr-help-or-harm-first-ever-gene-edited-babies ).
So, would be possible (technically and ethically ) to edit a new-born child?

Because of these limitations, I think that we may try to think other options like the one mentioned by Subash Chapagain where you can try to design a "drug" to keep silent the extra-copy.
However as also pointed out in his contribution there are some limitations, one of this being that also it is hard to control the silencing of just 1 copy out of 3 of the 21 chromosomes.

Another idea, but on this, I have to dig further in the literature, would be to identify the genes expressed on the chromosome(s) 21 because of which if over-expressed (as it happens in a contest in which you have an extra-copy of the chromosome) cause the condition. In this case, you may design a drug-cocktail keeping silent only that specific genes by using inhibitors and titrate them in a way you only silence a "certain amount" of their expression. This way you do not need to be allele-specific or chromosome-specific as you are acting downstream, so you just want that the final output (the protein) is lower ( regardless from which copy of the chromosome came).
Jamila a month ago
Hi Antonio Carusillo, thanks for the comment.

You’re right. The researchers used SNP to distinguish between the chromosomes and thus were able to delete only one chromosome, not all three. 😊

You bring up very good points. Treating the individual earlier does seem like it would be better, but of course, there would be substantial ethical implications associated with that! We would encounter the same problem using the XIST system because zinc fingers (a gene-editing system) are used to insert the XIST gene into chromosome 21. Due to this major hurdle, I wonder if any non gene-editing methods can be used silence or delete chromosomes.

Your idea is good. Instead of gene-editing, perhaps we could use drugs that stop the gene expression of genes that drive Down syndrome. Although, if we have to silence several genes that will be tough to do.

Future thoughts:
- Determine whether CRISPR or XIST treatments’ timing affects the overall therapeutic benefit in vitro and in vivo.
o If the treatment timing doesn’t impact the overall success significantly, then the ethical concerns associated with gene-editing in babies won’t be a problem.
- Find alternatives to gene-based treatment options that can silence or delete chromosomes.

Manel Lladó Santaeularia
Manel Lladó Santaeulariaa month ago
Hi Antonio Carusillo and Jamila , your contributions are very interesting and I agree with everything you said.

But a point that neither of you raised is that Down's Syndrome and syndromes caused by other chromosomal abnormalities are multisystemic disorders where several organs are deeply affected. In this case, efficient delivery of the gene editing therapeutic, which is already an issue when targeting a particular tissue, would be even more difficult because you are going to want to target several organs at the same time.

For this, maybe in patients who have already developed and have mental retardation and growth problems that cannot be solved, gene editing could be used to treat cardiac and pulmonary malfunctions, which are the main cause of early mortality and low quality of life in this kind of patients. This would be easier because you would only need to deliver the gene editing to that particular organ. Doesn't mean it would be easy, but definitely more feasible.

Developing an Inhibitory Cocktail to address Down-Syndrome

Antonio Carusillo
Antonio Carusillo Jan 21, 2021

[1]Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome Chang, Pishan et al. Cell Reports, Volume 30, Issue 4, 1152 - 1163.e4

[2]Gough G, O'Brien NL, Alic I, Goh PA, Yeap YJ, Groet J, Nizetic D, Murray A. Modeling Down syndrome in cells: From stem cells to organoids. Prog Brain Res. 2020;251:55-90. doi: 10.1016/bs.pbr.2019.10.003. Epub 2019 Nov 20. PMID: 32057312.

[3]Kurata, M., Yamamoto, K., Moriarity, B.S. et al. CRISPR/Cas9 library screening for drug target discovery. J Hum Genet 63, 179–186 (2018). https://doi.org/10.1038/s10038-017-0376-9

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