Možnosti zdravljenja hemoglobinopatij z uporabo Crispr/Cas9

Rak, Laura (author), Ogorevc, Jernej (mentor)

Mutacije v genu za β-globin (HBB) so vzrok za β-hemoglobinopatije, ki sodijo med najpogostejše avtosomalno recesivno podedovane monogenske bolezni na svetu. Moderne tehnologije preurejanja genoma kot je CRISPR/Cas9, nam omogočajo preurejanje krvotvornih matičnih celic (KMC), ki jih lahko uporabimo za zdravljenje npr. anemije srpastih celic in β-talasemije, ki predstavljata resen zdravstveni problem. Strategije preurejanja temeljijo na odvzemu bolniku lastnih KMC in preureditvi le teh ex vivo. Glavni strategiji preurejanja, ki se uporabljata sta korekcija mutacij, ki so odgovorne za bolezensko stanje v HBB genu s pomočjo homologne rekombinacije ali reaktivacija izražanja γ-globina, ki vodi v ponovno nastajanje fetalnega hemoglobina, kar lahko dosežemo z vnosom mutacij, ki delujejo na glavni regulator nastajanja γ-globina - BCL11A, ali pa na njegove eritroidno specifične ojačevalce. Po preurejanju genoma uspešno preurejene celice transplantiramo nazaj v bolnika. Možna pa je tudi uporaba alogene transplantacije, kjer se v bolnika transplantira zdrave celice histokompatibilnega darovalca. Dokaj enostavna izolacija in pridobivanje KMC sta omogočila napredek v razvoju genetskih terapij vse do kliničnih raziskav z obetavnimi rezultati.

• Language: Slovenian
• Keywords: CRISPR/Cas9, hemoglobinopatije, anemija srpastih celic, β-talasemija, krvotvorne matične celice
• Work type: Bachelor thesis/paper
• Typology: 2.11 - Undergraduate Thesis
• Organization: BF - Biotechnical Faculty
• Place of publishing: Ljubljana
• Publisher: [L. Rak]
• Year: 2021
• PID: 20.500.12556/RUL-129782
• UDC: 606:616-056.7:616.155.194:616.155.16:602.9(043.2)
• COBISS.SI-ID: 75447043
• Publication date in RUL: 08.09.2021

RAK, Laura, 2021, Možnosti zdravljenja hemoglobinopatij z uporabo Crispr/Cas9 [online]. Bachelor’s thesis. Ljubljana : L. Rak. [Accessed 25 April 2025]. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=129782

Secondary language

• Language: English
• Title: Potential treatments of hemoglobinopathies using Crispr/Cas9

Abstract

Mutations in the β-globin (HBB) gene are the cause of β-hemoglobinopathies, which are one of the most common autosomal recessive inherited monogenic disorder in the world. Modern genome editing technologies such as CRISPR/Cas9 allow us to edit hematopoietic stem cells (HSCs) in a way they can be used to treat disorders like sickle cell anemia and β-thalassemia, which represent a growing health problem. The editing strategy is based on collecting patient's own HSCs and perform editing ex vivo. The main rearrangement strategies are: correction of the mutation responsible for the disease in the HBB gene by homologous recombination or reactivation of γ-globin expression, which enables formation of fetal hemoglobin; this is achieved by inducing mutations in the main regulator of γ-globin formation - BCL11A or in its erythroid-specific enhancers. After gene editing, the successfully edited cells are transplanted back into the patient. It is also possible to use allogeneic transplantation, where healthy cells of a histocompatible donor are transplanted into the patient. Simple isolation and collection of HSCs have enabled the advancement of genetic therapies all the way to clinical trials with promising results.

• Keywords: CRISPR/Cas9, hemoglobinopathies, sickle cell anemia, β-thalassemia, hematopoietic stem cells