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How can we treat chromosomal abnormalities?

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

Jamila Jan 11, 2021
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Are there any techniques we could use to “fix” chromosomal abnormalities?

Most of the cells in our body have 23 pairs of chromosomes (46 chromosomes in total). We inherit half of our chromosomes from our mother and a half from our father. In terms of biological sex, females will have XX sex chromosomes, and males usually have XY sex chromosomes. Chromosomes contain genes that encode various proteins needed by our body. Therefore, the knowledge required by the body to develop and grow lies within our chromosomes.

Chromosomal abnormalities can arise when errors occur during cell division. The risk of chromosomal aberrations can increase due to maternal age and environmental factors. There are several types of chromosomal abnormalities; these can include:
  • Deletion - a part of the chromosome is deleted.
  • Duplication - a part of the chromosome has been duplicated.
  • Inversion - the genetic material is the wrong way around because the chromosome detached, inverted, then re-attached.
  • Translocation - a part of the chromosome is transferred to another chromosome.
  • Aneuploidy – is when there is an extra or missing chromosome.
Example of a chromosomal aberration
Down syndrome patients have an extra chromosome on chromosome 21 (trisomy 21). Trisomy 21 results in stunted growth, learning difficulties, characteristic facial features, and much more. Down syndrome has no cure. The patients just manage their disease with specialized education, speech therapy, hearing aids, etc.

Current treatments
At the moment, there are no treatments to “fix” or “treat” chromosomal abnormalities. Instead, treatments that tackle the disease symptoms are used. Therefore, the underlying cause of the health condition is still present. There is a great need to improve treatment options for individuals suffering from chromosomal abnormalities as chromosomal abnormalities can substantially impact patients’ quality of life.

What methods could we use to treat chromosomal aberrations?

[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
In a study reported in Nature in 2013, it was shown that normal gene expression can be restored in trisomy 21 cells by using the XIST, a non-coding RNA for silencing the extra chromosome.

The X-linked X-inactive-specific transcript (XIST) is a long noncoding RNA required for X -chromosome inactivation (XCI), in a process known as the dosage compensation- observed across all placental mammals. Dosage compensation ensures the equalization of most X-linked gene products between males (which have one X chromosome and hence a single dose of X-linked genes), and females (which have two X’s and hence double the dose of these genes). XIST initiates the process during early development by spreading in cis across the X chromosome from which it is transcribed. Xist RNA triggers gene silencing, recruits a number of chromatin-modifying factors, and dictates a massive structural reorganization of the X chromosome. The reported study built on the observation that XIST improved growth and differentiation of neural cells, inciting the hope that some deleterious effects of trisomy could be reversed -potentially applicable to rectify the otherwise incurable Down’s syndrome, a classic clinically implied case of trisomy.

Gene expression studies have shown that in the case of trisomy 21, not only chromosome 21-linked genes, but genes on other chromosomes are also disrupted. This suggested that the effects of this chromosomal aberration on the transcriptome are wider than expected. Evolutionarily, mammals evolved different feed-forward mechanisms of dosage compensation to achieve correct gene expression- regulation of X-chromosome being one. X upregulation in males(to increase expression) and X-inactivation by silencing in females are hence the equivalent mechanisms in an attempt for the dosage compensation .

Lawrence et. al. proposed that the mechanism of dosage compensation by X-inactivation could be appropriated to rectify trisomy 21. Since XIST RNA spreads in cis even when inserted/attached to an autosome, its silencing power could be used to silence one chromosome 21.

The group used a ZFN (Zinc Finger Nuclease) system to target chromosome 21, and they brought about insertion and induction of the large genomic fragment consisting of XIST in trisomic induced pluripotent stem (iPS) cells. Afterwards, they observed the accumulation of repressive histone modifications, along with DNA methylation of CpG islands in the induced (doxycycline induction was used) cells. The epigenetic changes and resultant silencing was stable in the differentiated cells. Nevertheless, whether the silencing is sustained after many cell divisions is yet to be determined. In a transgenic mouse model with XIST inserted in an autosome, the deactivation is lost over time- the silencing is patchy and has translocations. In contrast, the X-chromosome inactivation is stable- suggesting that X-specific elements which are absent in autosomes are crucial for the stable silencing. Another finding by the group was that the cells grow better after XIST insertion on chromosome 21 in comparison to the control of trisomic cells, and there is the more efficient formation of neural rosettes. This has been attributed to the fact that XIST insert was within the DYRK1A gene, a critical player for neural differentiation.

With these observations, the question that arises obviously is whether XIST insertion into any autosome can be effectively applied for rescuing trisomy? At least at the cellular level, this seems achievable, albeit posing serious challenges to apply in vivo.

As compared to silencing by XIST, complete loss/removal of the extra chromosome would be preferable due to the issues of stability. However, XIST approach has its versatility due to the system being inducible. In mice models, hematopoietic precursor cells are permissive to X-inactivation by Xist induction . Still, induction and silencing might be difficult in other cell types. Hence, to use this approach, the effective regulatory system would have to be designed if only parts of a rearranged chromosome were to be silenced. Some genes on the X chromosome escape silencing , and such genes are mostly grouped within domains protected from epigenetic changes associated with silencing (including Xist coating). Once we understand such insulator elements that separate these ‘protected’ domains, then maybe it would be easier to design ways to control and regulate XIST spreading .

[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

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Jamila 4 years 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?

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Subash Chapagain
Subash Chapagain4 years 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.
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Jamila 4 years 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.
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Using CRISPR to treat trisomies

Jamila Jan 12, 2021
Zuo and colleagues were able to delete the Y chromosome in vitro and in vivo (in mice) using chromosomal editing. The team deleted the Y chromosome by making several cuts at chromosome-specific repeat sequences using CRISPR-Cas9.

Zuo conducted similar research for trisomy 21. It is known that Down syndrome patients have an extra chromosome at chromosome 21. Zuo and colleagues deleted the extra chromosome from the Down syndrome patient's cells by targeting repeated sequences found only in chromosome 21. After editing, 15% of the cells showed the presence of 2 x chromosome 21, suggesting that the extra chromosome had been successfully deleted in some cells. No severe off-target effects were reported, but several off-target effects were present. Chromosomal editing has the potential to treat trisomies. However, the technology is still in its infancy at the moment and requires to be optimised because there are off-target effects, and the on-target efficiency needs to be improved.

My thoughts moving ahead:
  • I wonder how the extra chromosome was specifically targeted without impacting all three of the chromosomes in the Down syndrome patient's cells?
  • Would partial chromosomal editing ameliorate the disease severity?
  • Would randomly deleting a chromosome mid-life have lethal consequences?

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

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Antonio Carusillo
Antonio Carusillo4 years 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).
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Jamila 4 years 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.

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Manel Lladó Santaeularia
Manel Lladó Santaeularia3 years 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.
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Developing an Inhibitory Cocktail to address Down-Syndrome

Antonio Carusillo
Antonio Carusillo Jan 21, 2021
Among the Chromosomal Abnormalities, with an incidence of 1 in 800 newborns, probably the Chromosome 21 Trisomy – commonly called Down Syndrome – it is the most known. This Chromosomal Abnormality is caused by an extra copy of the chromosome 21 which results in the supraphysiological dosage of the genetic material held by the extra-copy. A single copy of chromosome 21 carries up to 200 different genes.
Their presence causes a tremendous genetic unbalance whose main consequence is an impact on the correct cognitive development of the one who is affected by this condition.
As discussed already in this session, gene editing may sound like an option to eliminate this extra copy. As pointed out by (Jamila), CRISPR has been used in vitro and in vivo – mice model- to delete the extra copy of chromosome 21.

However, even if effective, its translation to humans poses some questions:
- How to ensure that only one of the three chromosomes 21 is deleted?
- Which is the earliest time point – excluding intervention at the embryo level - at which the CRISPR-based therapy should be administrated to be effective?
- Can CRISPR reach a sufficient number of cells to revert the early symptoms of the condition?

Although more and more CRISPR based therapies are entering human testing, still such disorders that kick in since the very early stage of life of the patient may be beyond the reach of CRISPR at the moment.
For these reasons, we may think about treatments aiming to contain or ameliorate the supraphysiological condition caused by the extra-copy of chromosome 21. Meaning, try to identify among the 200 different genes encoded by the exon 21, which are the ones driving most of the effects observed in the Down Syndrome patient.
This way, we may think about using specific inhibitors acting at the transcript (mRNA) or protein level to de-escalate the supraphysiological situation, hopefully ameliorating or curing the major symptoms. This strategy may be doable as it does not require to be allele-specific as in the case of deleting an entire chromosome, drugs compatible with children can be developed and discontinued whenever a side-effect may arise. This would be not possible with CRISPR, of course, contrary to CRISPR it is not a “one-shot” treatment, but it is less risky. This is also an important cause, although a serious condition, thanks to improvement in health-care and social assistance, Down patient life expectancy is enormously improved and they can lead a life close to normal. Thereby, it is not considered a life-threatening condition that may require “extreme means”.
Regarding this idea, we may look at a recent paper published in the Cell , where they have been studying 3 different Down-syndrome mice models to interrogate the possible driver cause of cognitive deficits observed in the patient. They indeed asked themselves if specific genes or sequence repetitions may be the driver cause. Using different behavioral tests they could identify genes like ADAR2, S100B, CSTB, PRMT2, and TRPM2, which are already known do be involved in neurodevelopment. On the other hand, they also observed that in one the model tested, reducing the expression of the Dyrk1a did not rescue the cognitive impairment of the mice model assessed via spatial alternation task. This is an important observation as Dirk1a inhibitors are being already tested as a possible treatment for some of the symptoms of Down Syndrome. This may be because, as we may expect, other genes when over-expressed contribute to the overall phenotype, and thereby a strategy aiming at inhibiting multiple genes at the same time could be effective at counteracting the symptoms of this condition.

So we may think, to identify the possible targets - or a combination of candidates - via RNAi screening or also using CRISPR-libraries. The first one uses hundreds of different small-hairpin RNA and the second, single-guide RNAs.
Both methods allow screening hundreds of different genes simultaneously.
Currently, there are different in vitro models to study Down Syndrome using, for example, Embryonic Stem Cells (ESCs), or Induced Pluripotent Stem Cells (iPSCs), or even organoids .
We may think, for example, to construct a library containing all the genes encoded by Chromosome 21 and to select the ones already known to be involved in brain development and/ or associated with cognitive impairment.
At this point, you may start targeting them one by one and then combinations of 2 or more genes at the same time.
From this, you will get a huge amount of data, which once analyzed and untangled may lead to a few dozens of genes to be tested in a proper mice model.
This way starting from a cell line model you may narrow down the possible candidates and then further explore them in vivo.

This strategy is already applied in drug discovery for cancer and it may also be applied to other conditions characterized by Chromosomal Abnormalities.

[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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