Treatments that modify your DNA: Dangerous?

Alicia Alonso · 15-03-2022 11:00 · Science Chronicles

With the fast development of the COVID-19 vaccines based on a new revolutionary technology of RNA delivery, new topics for discussion sprung up in the general population. Concerns over whether these vaccines could modify our DNA or not spread rapidly, encouraged by anti-vaxxers and self-confident people with little or no scientific knowledge who saw an opportunity for their moment of glory.

It goes without saying that the vaccines don’t alter your DNA, and that is a discussion beyond the topic of this article. However, the bigger question is: can modern medicine alter your DNA? And if so, is that necessarily a bad thing?

Let’s talk about gene therapy.

First of all: what is DNA? DNA is formed of chains of smaller units called nucleotides. DNA is contained into the nucleus of almost all the cells of our organism . Nucleotides act like a coding language, that can be transferred into messenger RNA (mRNA). This process is called transcription. From the mRNA, the nucleotides-code can be read by the ribosomes, which translates it into amino acids, which are the small units (“the bricks”) that form proteins (Figure 1). Ultimately, all the processes of our organism are carried out by proteins. All the structural components are also formed by proteins. They are, therefore, extremely important for our functioning and living.  

Figure  1. All cells of the body contain a nucleus. This contains the DNA, packed into chromosomes. The DNA is formed by two complementary chains which are made up of nucleotides. The DNA is transcribed into mRNA through a process called "transcription". Each group of 3 nucleotides of the mRNA is called “codon”. These codons are read by the ribosomes (not shown in the picture) and translated into amino acids, which form proteins. Image created with biorender.

Many human diseases are suspected to have a genetic cause. That means that a mutation of the DNA, in other words a change in the sequence of nucleotides, is responsible for the developing of the disorder. This is best known for monogenic diseases, that is, diseases caused by mutations in just one gene.  These disorders are hereditary, which means they can be transferred to offspring.  

Some examples of this type of disease are hereditary amyloidosis, spinal muscular atrophy, or β-thalassemia.

Historically, such genetic disorders have had very few options for treatment, and the available therapies had always only been able to simply alleviate the symptoms, but could never address the underlying problem. That is because until recently, being able to edit DNA was only possible in science fiction.

However, in the last decade, with the expanding knowledge in the field of genetics and the evolution of technology, there is new hope for the treatment of these disorders.

We must clarify that the term “gene therapy” usually includes different therapeutic strategies that are not always aimed to modify the DNA, but also the RNA (Figure 2). However, strictly speaking, this last group should not be considered as gene therapy.

Figure  2. In this image we can see a mutation in the DNA, which is also present in the mRNA. The result is an aberrant protein due to the change of one amino acid (glycine [gly] to aspartate [asp]). We could try to revert these changes at the level of the DNA (through gene therapy) or at the level of the mRNA (RNA-based therapy). Image created with biorender.

When there is a mutation in the DNA, this would be transcribed into the mRNA, and then translated into an amino acid. This could alter the function of the protein. This alteration could have different consequences. It could, for example, mean that the protein is no longer active and gets degraded by the cell. But it could also mean that it becomes hyperactive, which is also harmful. It could also produce an altered protein that can not be degraded and therefore accumulates inside the cell until it dies. All of them are negative consequences, but the way to approach them will be different. There are strategies at the level of RNA and at the level of DNA.

To give an example of RNA-based therapy, let’s talk about Patisiran and hereditary transthyretin amyloidosis.

Hereditary transthyretin amyloidosis is a rare, progressive, and life-threatening disease. It is caused by mutations in a gene called TTR, which encodes the protein transthyretin. This protein is secreted by the liver, and its function is to transport vitamin A through the body. However, when the TTR gene is mutated, transthyretin accumulates in deposits in the liver, the nerve system, and the heart, among others, producing malfunctioning of these organs. Patients develop difficulty walking, dizziness, diarrhea, bladder disturbances and eventually heart failure and death. Patisiran is a small molecule of RNA (called “RNA interference” or “RNAi”) that binds to the mRNA and with help of a protein complex called RISC (RNA-induced silencing complex), cleaves the mRNA, preventing the production of the transthyretin, therefore preventing the accumulation (Patisiran kind of tells the RISC “Hey buddy! Cut here!”). This smart treatment approach has changed the lives of people with this disorder like no other therapy ever had.

Another dramatic example of RNA-based therapy is Nusinersen, a drug developed for Spinal Muscular Atrophy (SMA). SMA is a deadly disease that could start in adulthood, although the most severe forms begin in the first months of life. The neurons in the spinal cord begin to die, and as they do so, the baby stops moving his or her legs and arms, has problems feeding because of loss of suction strength, and eventually dies due to respiratory failure, usually before 2 years of age (for the most severe forms).

The cause of SMA is a mutation in the gene SMN1 (“survival motor neuron 1”… a very descriptive name for this gene, for the following reason). The mutated gene can not produce its protein, SMN, which causes the neurons to die. The mechanism of action of Nusinersen is a bit different from Patisiran. Instead of binding to SMN1, it binds to another very similar region of the mRNA (SMN2) which also encodes SMN, but one of a lower quality, that does not work as well as the protein produced by SMN1. Nusinersen slightly changes the mRNA of SMN2 so that it encodes a good quality SMN protein. When the clinical trial of Nusinersen took place, the preliminary results after just 6 months of treatment were so overwhelmingly positive that they prompted early termination of the study and switched the patients that were receiving placebo to the medication group. These dramatic results meant that toddlers who would not have been able to keep their heads upright were not only doing so, but also learning to roll, sit and crawl (Figure 3). Nusinersen has therefore changed the history of this disease forever.   

Figure  3. Results of the motor milestones in patients from the clinical trial of Nusinersen. In blue, the patients who received the medicine, and in grey, the patients who received placebo (none of the patients under placebo reached any of the motor milestones). Graph from Nusinersen versus sham control in infantile onset spinal muscular atrophy. N Engl J Med 2017; 377:1723-1732

The main disadvantage of Nusinersen is that it must be administered directly in the fluid that surrounds the spinal cord via lumbar puncture, bringing discomfort to the patient.

Nusinersen is not the only treatment for SMA. Some years later, this disease became one of the first disorders to get an approved DNA-based gene therapy: Onasemnogene abeparvovec. This impossible-to-pronounce drug is better known for its commercial name: Zolgensma®.  Zolgensma is administered intravenously in only one dose. It contains the SMN1 gene packed into an adeno-associated virus that has been stripped of its viral DNA. This viral vector gets into the Central Nervous System, where it is captured by the neurons, and, once inside, it liberates the SMN1-gene. In the cell, the gene can be transcribed into mRNA and translated into the SMN protein (Figure 4). This therapy became famous in Belgium through the story of Pia, a baby with SMA born in Antwerp (link to the story: Baby Pia: Almost 1m Belgians pay for life-saving drug - BBC News).

Figure  4. Zolgensma contains adenoviruses with the SMN1 gene. Once they reach the Central Nervous System they get inside the cell and liberate the DNA into the nucleus, where it can use the machinery of the cell to produce normal functioning SMN protein.

SMA is not the only disease with approved gene-therapy. β- thalassemia is caused by mutations in the hemoglobin gene HBB, which encodes a subunit of hemoglobin, an essential protein of red blood cells. People with β- thalassemia have an impaired production of these cells, suffering from profound anemia. In the most severe cases, they are completely dependent on periodic blood transfusions for their whole lives. Because all blood cell types come from the same stem cell (figure 5), a gene-therapy approach to cure this disease would be to extract the stem cells from the patient (which carry the mutation in the HBB gene), modify them in vitro introducing the healthy copy of the gene, and injecting them back into the patient. This is exactly the action mechanism of Zynteglo®, the first gene therapy approved for β- thalassemia. In the phase I-II clinical trial, most patients could stop receiving blood transfusions, and the ones who still needed them could decrease the volume of these by 73%, a dramatic result! For these patients Zynteglo® means, not only feeling healthier but also freedom from frequent visits to the hospital for transfusions.

Figure  5. Set of all blood cells and their progenitors. All the different cell types come from the same stem cell.

These are only a few examples of what science has been able to do in recent History. The more we know about how our body works, the more strategies we can use to fix the diseases that come to us. Gene therapy is an exciting and expanding field, and there is no reason to be afraid, instead, there are many reasons to be hopeful.

 

Bibliography:

  1. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang C-C, Ueda M, Kristen A V., et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11–21.
  2. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723–32.
  3. Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284–93.
  4. Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil J-A, Hongeng S, et al. Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia. N Engl J Med. 2018;378(16):1479–93.
  5. Rattananon P, Anurathapan U, Bhukhai K, Hongeng S. The Future of Gene Therapy for Transfusion-Dependent Beta-Thalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells. Front Pharmacol. 2021 Oct 1;12:2613.

 

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شركة سكاي نقل العفش , 4 days ago


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http://www.domyate.com/2019/09/05/best-company-transfer-furniture-khamis-mushit/ افضل شركات نقل اثاث بخميس مشيط
http://www.domyate.com/2019/09/05/company-transfer-furniture-khamis-mushit/ شركات نقل اثاث بخميس مشيط
http://www.domyate.com/category/%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D8%AC%D8%AF%D8%A9/ نقل عفش جدة
http://www.domyate.com/2019/09/25/movers-furniture-from-jeddah-to-jordan/ نقل عفش من جدة الي الاردن
http://www.domyate.com/2019/10/03/price-cleaning-tanks-in-jeddah/ اسعار شركات تنظيف خزانات بجدة
http://www.domyate.com/2019/09/25/movers-furniture-from-jeddah-to-egypt/ نقل عفش من جدة الي مصر
http://www.domyate.com/2019/09/24/movers-furniture-from-jeddah-to-lebanon/ نقل عفش من جدة الي لبنان
http://www.domyate.com/2019/09/22/%d8%a3%d9%86%d8%ac%d8%ad-%d8%b4%d8%b1%d9%83%d8%a7%d8%aa-%d9%86%d9%82%d9%84-%d8%a7%d8%ab%d8%a7%d8%ab-%d8%a8%d8%ac%d8%af%d8%a9/ شركات نقل اثاث بجدة
http://www.domyate.com/2019/09/22/best-company-movers-jeddah/ افضل شركات نقل اثاث جدة
http://www.domyate.com/2019/09/22/company-transfer-furniture-yanbu/ شركات نقل العفش بينبع
http://www.domyate.com/2019/09/21/taif-transfer-furniture-company/ شركة نقل عفش في الطائف
http://www.domyate.com/2019/09/21/%d8%b4%d8%b1%d9%83%d8%a7%d8%aa-%d9%86%d9%82%d9%84-%d8%a7%d9%84%d8%b9%d9%81%d8%b4/ شركات نقل العفش
http://www.domyate.com/2019/09/21/%d8%b7%d8%b1%d9%82-%d9%86%d9%82%d9%84-%d8%a7%d9%84%d8%b9%d9%81%d8%b4/ طرق نقل العفش
http://www.domyate.com/2019/09/20/%d8%ae%d8%b7%d9%88%d8%a7%d8%aa-%d9%86%d9%82%d9%84-%d8%a7%d9%84%d8%b9%d9%81%d8%b4-%d9%88%d8%a7%d9%84%d8%a7%d8%ab%d8%a7%d8%ab/ خطوات نقل العفش والاثاث
http://www.domyate.com/2019/09/20/best-10-company-transfer-furniture/ افضل 10 شركات نقل عفش
http://www.domyate.com/2019/09/20/%d9%83%d9%8a%d9%81-%d9%8a%d8%aa%d9%85-%d8%a7%d8%ae%d8%aa%d9%8a%d8%a7%d8%b1-%d8%b4%d8%b1%d9%83%d8%a7%d8%aa-%d9%86%d9%82%d9%84-%d8%a7%d9%84%d8%b9%d9%81%d8%b4-%d9%88%d8%a7%d9%84%d8%a7%d8%ab%d8%a7%d8%ab/ اختيار شركات نقل العفش والاثاث
http://www.domyate.com/2019/09/20/cleaning-company-house-taif/ شركة تنظيف منازل بالطائف
http://www.domyate.com/2019/09/20/company-cleaning-home-in-taif/ شركة تنظيف شقق بالطائف
http://www.domyate.com/2019/09/20/taif-cleaning-company-villas/ شركة تنظيف فلل بالطائف
http://www.domyate.com/ شركة نقل عفش
http://www.domyate.com/2017/09/21/%D9%86%D9%82%D9%84-%D8%A7%D9%84%D8%B9%D9%81%D8%B4-%D9%88%D8%A7%D9%84%D8%AA%D8%AE%D8%B2%D9%8A%D9%86/ نقل العفش والتخزين
http://www.domyate.com/2016/07/02/transfer-furniture-dammam شركة نقل عفش بالدمام
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http://www.domyate.com/2016/06/05/transfer-furniture-jeddah/ شركة نقل عفش بجدة
http://www.domyate.com/2017/08/10/movers-company-mecca-naql/ شركات نقل العفش بمكة
http://www.domyate.com/2016/06/05/transfer-furniture-mecca/ شركة نقل عفش بمكة
http://www.domyate.com/2016/06/05/transfer-furniture-taif/ شركة نقل عفش بالطائف
http://www.domyate.com/2016/06/05/transfer-furniture-riyadh/ شركة نقل عفش بالرياض
http://www.domyate.com/2016/06/05/transfer-furniture-yanbu/ شركة نقل عفش بينبع
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http://www.domyate.com/2015/08/30/furniture-transport-company-in-almadinah/ شركة نقل عفش بالمدينة المنورة
http://www.domyate.com/2016/06/05/transfer-furniture-medina-almonawara/ شركة نقل عفش بالمدينة المنورة
http://www.domyate.com/2018/10/13/%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D8%AC%D8%AF%D8%A9-%D8%B4%D8%B1%D9%83%D8%A7%D8%AA-%D9%86%D9%82%D9%84-%D9%85%D9%85%D9%8A%D8%B2%D8%A9/ نقل عفش بجدة
http://www.domyate.com/2016/07/22/%d8%a7%d8%b1%d8%ae%d8%b5-%d8%b4%d8%b1%d9%83%d8%a9-%d9%86%d9%82%d9%84-%d8%b9%d9%81%d8%b4-%d8%a8%d8%a7%d9%84%d9%85%d8%af%d9%8a%d9%86%d8%a9-%d8%a7%d9%84%d9%85%d9%86%d9%88%d8%b1%d8%a9/ ارخص شركة نقل عفش بالمدينة المنورة
http://www.domyate.com/2016/07/25/%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D8%A8%D8%A7%D9%84%D9%82%D8%B5%D9%8A%D9%85/ شركة نقل عفش بالقصيم
http://www.domyate.com/2016/07/25/%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D8%A8%D8%AE%D9%85%D9%8A%D8%B3-%D9%85%D8%B4%D9%8A%D8%B7/ شركة نقل عفش بخميس مشيط
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http://www.domyate.com/2016/07/23/%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D8%A8%D8%AA%D8%A8%D9%88%D9%83/ شركة نقل عفش بتبوك

شركة نقل عفش بالمدينة المنورة , 4 days ago


شركة كيان لنقل العفش بالرياض والمدينة المنورة وجدة ومكة والطائف والدمام تقديم لكم دليل كامل لشركات نقل العفش بالمملكة العربية السعودية
http://mycanadafitness.com/ شركة كيان لنقل العفش
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http://mycanadafitness.com/movingfurnitureriyadh.html شركة نقل اثاث بالرياض
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http://mycanadafitness.com/movingfurnituredammam.html شركة نقل اثاث بالدمام
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http://mycanadafitness.com/movingfurniturekharj.html شركة نقل اثاث بالخرج
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http://mycanadafitness.com/movingfurnitureabha.html شركة نقل اثاث بابها
http://mycanadafitness.com/movingfurniturenajran.html شركة نقل اثاث بنجران
http://mycanadafitness.com/movingfurniturejazan.html شركة نقل اثاث بجازان
http://mycanadafitness.com/movingfurnitureasir.html شركة نقل اثاث بعسير
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http://mycanadafitness.com/companis-moving-riyadh.html شركات نقل العفش بالرياض
http://mycanadafitness.com/cars-moving-riyadh.html سيارات نقل العفش بالرياض
http://mycanadafitness.com/company-number-moving-riyadh.html ارقام شركات نقل العفش بالرياض
http://mycanadafitness.com/company-moving-jeddah.html شركات نقل العفش بجدة
http://mycanadafitness.com/price-moving-jeddah.html اسعار نقل العفش بجدة
http://mycanadafitness.com/company-moving-mecca.html شركات نقل العفش بمكة

شركة كيان لنقل العفش , 4 days ago


http://fullservicelavoro.com/ شركة ريلاكس لنقل العفش والاثاث
http://fullservicelavoro.com/2019/01/07/transfer-movers-taif-furniture/ شركة نقل عفش بالطائف
http://fullservicelavoro.com/2019/01/08/transfer-movers-riyadh-furniture/ شركة نقل عفش بالرياض
http://fullservicelavoro.com/2019/01/08/transfer-movers-jeddah-furniture/ شركة نقل عفش بجدة
http://fullservicelavoro.com/2019/01/01/transfer-and-movers-furniture-mecca/ شركة نقل عفش بمكة
http://fullservicelavoro.com/2019/01/07/transfer-movers-madina-furniture/ شركة نقل عفش بالمدينة المنورة
http://fullservicelavoro.com/2019/01/07/transfer-movers-khamis-mushait-furniture/ شركة نقل عفش بخميس مشيط
http://fullservicelavoro.com/2019/01/09/transfer-movers-abha-furniture/ شركة نقل اثاث بابها
http://fullservicelavoro.com/2019/01/07/transfer-movers-najran-furniture/ شركة نقل عفش بنجران
http://fullservicelavoro.com/2019/01/16/transfer-movers-hail-furniture/ ِشركة نقل عفش بحائل
http://fullservicelavoro.com/2019/01/16/transfer-movers-qassim-furniture/ شركة نقل عفش بالقصيم
http://fullservicelavoro.com/2019/02/02/transfer-movers-furniture-in-bahaa/ شركة نقل عفش بالباحة
http://fullservicelavoro.com/2019/01/13/transfer-movers-yanbu-furniture/ شركة نقل عفش بينبع
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http://fullservicelavoro.com/2019/01/07/transfer-movers-elkharj-furniture/ شركة نقل عفش بالخرج
http://fullservicelavoro.com/2019/01/07/transfer-movers-baqaa-furniture/ شركة نقل عفش بالبقعاء
http://fullservicelavoro.com/2019/02/05/transfer-furniture-in-jazan/ شركة نقل عفش بجازان

شركة ريلاكس لنقل العفش والاثاث , 4 days ago



https://sites.google.com/view/movers-riyadh/
https://sites.google.com/view/movers-riyadh/movers-mecca
https://sites.google.com/view/movers-riyadh/home
https://sites.google.com/view/movers-riyadh/movers-jedaah-elhamdniah
https://sites.google.com/view/movers-riyadh/movers-yanbu
https://sites.google.com/view/movers-riyadh/movers-najran
https://sites.google.com/view/movers-riyadh/movers-Jizan
https://sites.google.com/view/movers-riyadh/jazan
https://sites.google.com/view/movers-riyadh/taif
https://sites.google.com/view/movers-riyadh/moversjeddah
https://sites.google.com/view/movers-riyadh/movers-abha
https://sites.google.com/view/movers-riyadh/movers-elahsa
https://sites.google.com/view/movers-riyadh/movers-elkhobar
https://sites.google.com/view/movers-riyadh/movers-elkharj
https://sites.google.com/view/movers-riyadh/movers-elmadina-elmnowara
https://sites.google.com/view/movers-riyadh/movers-eljubail
https://sites.google.com/view/movers-riyadh/movers-elqassim
https://sites.google.com/view/movers-riyadh/movers-hafrelbatin
https://sites.google.com/view/movers-riyadh/movers-elbaha
https://sites.google.com/view/movers-riyadh/movers-jeddah
https://sites.google.com/view/movers-riyadh/movers-dammam
https://sites.google.com/view/movers-riyadh/movers-taif
https://sites.google.com/view/movers-riyadh/movers-burydah
https://sites.google.com/view/movers-riyadh/movers-tabuk
https://sites.google.com/view/movers-riyadh/movers-hail
https://sites.google.com/view/movers-riyadh/movers-khamis-mushait
https://sites.google.com/view/movers-riyadh/movers-rabigh
https://sites.google.com/view/movers-riyadh/madina
https://sites.google.com/view/movers-riyadh/mecca
https://sites.google.com/view/movers-riyadh/dammam
https://sites.google.com/view/movers-riyadh/jeddah
https://sites.google.com/view/movers-riyadh/ahsa
https://sites.google.com/view/movers-riyadh/cleaning-mecca

ارخص شركة نقل عفش واثاث بمكة , 4 days ago


https://zlidein.com/read-blog/97062
https://zlidein.com/read-blog/97063
https://zlidein.com/read-blog/97071
https://zlidein.com/read-blog/99326
https://www.skreebee.com/read-blog/110085
https://telegra.ph/%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D9%85%D9%86-%D8%AC%D8%AF%D8%A9-%D8%A7%D9%84%D9%89-%D8%AC%D8%A7%D8%B2%D8%A7%D9%86-07-12
https://webyourself.eu/blogs/25649/%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D9%85%D9%86-%D8%AC%D8%AF%D8%A9-%D8%A7%D9%84%D9%89-%D8%AC%D8%A7%D8%B2%D8%A7%D9%86
https://www.merexpression.com/read-blog/21528
https://www.rolonet.com/blogs/89146/%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D9%85%D9%86-%D8%AC%D8%AF%D8%A9-%D8%A7%D9%84%D9%89-%D8%AC%D8%A7%D8%B2%D8%A7%D9%86
https://oktob.io/posts/41814
https://companymovers9.wordpress.com/
https://newmoverdotblog.wordpress.com/
https://qwasdew.wordpress.com/
https://wordpress.com/home/gigisaad.wordpress.com

https://webyourself.eu/blogs/26016/%D8%A7%D9%81%D8%B6%D9%84-%D8%B4%D8%B1%D9%83%D8%A9-%D9%86%D9%82%D9%84-%D8%B9%D9%81%D8%B4-%D8%AC%D8%AF%D8%A9-%D8%A7%D8%A8%D8%AD%D8%B1-%D8%A7%D9%84%D8%B4%D9%85%D8%A7%D9%84%D9%8A%D8%A9

https://oktob.io/posts/41908
https://www.domyate.com/2022/06/14/why-emc-mee-company-to-transfer-furniture-to-to-jeddah/
https://www.domyate.com/2022/06/12/best-nakl-afsh-jeddah/
https://www.domyate.com/2022/06/12/%d9%83%d9%8a%d9%81%d9%8a%d8%a9-%d9%81%d9%83-%d9%88%d8%aa%d8%b1%d9%83%d9%8a%d8%a8-%d8%a7%d9%84%d8%b9%d9%81%d8%b4-%d9%88%d8%a7%d9%84%d8%a7%d8%ab%d8%a7%d8%ab-%d8%a8%d8%ac%d8%af%d8%a9/

https://zlidein.com/read-blog/99328

https://telegra.ph/%D8%A7%D9%81%D8%B6%D9%84-%D8%B4%D8%B1%D9%83%D8%A9-%D8%AA%D9%86%D8%B8%D9%8A%D9%81-%D9%85%D9%83%D9%8A%D9%81%D8%A7%D8%AA-%D8%A8%D9%85%D9%83%D8%A9-07-17


http://html.net.linux17.wannafindserver.dk/forums/viewtopic.php?f=6&t=447291&sid=d49bfa79507d1da5e63e18cadb51c609
https://www.carookee.de/forum/Retinoblastom-Forum/32167082?mp=49083704862d5f02883b054f8275606a980b0ddf6bde4bc1a0c4b5&mps=%26%231588%3B%26%231585%3B%26%231603%3B%26%231577%3B+%26%231606%3B%26%231602%3B%26%231604%3B+%26%231593%3B%26%231601%3B%26%231588%3B+%26%231575%3B%26%231604%3B%26%231589%3B%26%231602%3B%26%231585%3B+%26%231575%3B%26%231604%3B%26%231583%3B%26%231608%3B%26%231604%3B%26%231610%3B#32167082
http://html.net.linux17.wannafindserver.dk/forums/viewtopic.php?f=5&t=447319&sid=02b7bb5d454a63d0454daad5ff0e8fa3
https://www.carookee.de/forum/Retinoblastom-Forum/32167083?mp=156822404062d6023635638289af31b90d4f5bbea03aea79dc802ca&mps=%26%231588%3B%26%231585%3B%26%231603%3B%26%231577%3B+%26%231578%3B%26%231606%3B%26%231592%3B%26%231610%3B%26%231601%3B+%26%231605%3B%26%231603%3B%26%231610%3B%26%231601%3B%26%231575%3B%26%231578%3B+%26%231576%3B%26%231605%3B%26%231603%3B%26%231577%3B#32167083
https://www.carookee.de/forum/Retinoblastom-Forum/32167084?mp=156822404062d604da7583a085d6df59451e00fbf675ffe4d767997&mps=%26%231588%3B%26%231585%3B%26%231603%3B%26%231577%3B+%26%231578%3B%26%231606%3B%26%231592%3B%26%231610%3B%26%231601%3B+%26%231582%3B%26%231586%3B%26%231575%3B%26%231606%3B%26%231575%3B%26%231578%3B+%26%231576%3B%26%231582%3B%26%231605%3B%26%231610%3B%26%231587%3B+%26%231605%3B%26%231588%3B%26%231610%3B%26%231591%3B#32167084
https://www.carookee.de/forum/Retinoblastom-Forum/32167085?mp=156822404062d60ab56d77ab711e09fefce9f81dfa2064fdad6969e&mps=%26%231588%3B%26%231585%3B%26%231603%3B%26%231577%3B+%26%231606%3B%26%231602%3B%26%231604%3B+%26%231593%3B%26%231601%3B%26%231588%3B+%26%231605%3B%26%231606%3B+%26%231580%3B%26%231583%3B%26%231577%3B+%26%231575%3B%26%231604%3B%26%231609%3B+%26%231580%3B%26%231575%3B%26%231586%3B%26%231575%3B%26%231606%3B#32167085

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شركات نقل الاثاث , 4 days ago

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