Last week we spoke about the discovery of CRISPR and the impact it has made on the scientific community (read last week’s post here). In short, the discovery of CRISPR, began in a lab in the late 1980s investigating the role of viruses in bacteria. Since then scientists all over the world have all contributed to the understanding of CRISPR and its applications in disease treatment and prevention.
CRISPR has since been used to create disease models; and targeting viruses. CRISPR in biomedicine has been particularly targeting myogenesis, inflammation and cancer and haemoglobin disorders. Approximately 5% of people in the world carry traits for haemoglobin disorders – the most prominent being sickle-cell disease (SCD) and thalassemia. SCD is a monogenic disease caused by a single point mutation (substitution of the 6th amino acid from A to T in the β-globin protein ) (pictured). This substitution results in the production of valine instead of glutamic acid causing sickled haemoglobin. This mutated haemoglobin can ultimately cause pain and anemia in SCD patients, due to the decreased delivery of oxygen to bones, muscles and organs.
The current ‘cure’ for SCD is allogeneic hematopoietic stem cell transplantation - proving effective in less than 15% of patients and carrying possible risks. The search continues for a more appropriate cure for SCD. In 2016, DeWitt et al used CRISPR-Cas9 gene editing to modify hematopoetic stem cells (HPSCs) from SCD patients. CD34+ HSPCs were treated using CRISPR-Cas9 assisted gene-editing to replace the SCD mutation and results were promising - showing that these treated stem cells showed less sickle haemoglobin protein in mice.
Such a discovery is a hopeful step forward in sickle-cell research as the findings are equipping the possibility of treating the cause of the disease rather than current therapy which focuses on managing the symptoms. As SCD is a single-base change disease, it would be assumed that CRISPR-Cas9’s gene-editing ability would be quickly adopted as a treatment for SCD. This was not the case when DeWitt et al (2016) found that even with modifications to the CRISPR-Cas9 editing technique, Cas9 was effective in correcting 25% alleles in human cells with 5% of these alleles producing normal haemoglobin in mice.
Moving forward scientists are now looking at targeting fetal-haemoglobin in patients as it is prone to sickling. By suppressing the production of fetal haemoglobin through CRISPR-Cas9 gene editing there may be the potential to reduce the production of sickle-shaped haemoglobin.
Park et al (2016) reports that in vivo autologous transplantation yields up to a 35% success in gene repair. These findings are promising, but not a solution. Now proof-of-concept has been achieved, the next step in curing SCD is improving efficiency and optimising delivery to those in need of treatment.
Our last two posts have shown how CRISPR is versatile and widely applicable biological application that can be assumed to have limitless applications. The combined knowledge of the human genome and the power of genetic modification could mean that CRISPR is available as a therapeutic tool as well as a mechanism of prevention in a vast number of diseases.
By Tomi Akingbade, Founder