The End of Genetic Disease?

14th February 2023 - Last modified 18th October 2023

By Bree Foster PhD, Science Writer

Every day, science fiction moves closer to becoming science reality. With the advancement of gene editing to include single base changes, the way we treat certain diseases could be revolutionised. Could this technology mean the end of genetic disease?

The beginning of a promising future             

Genome editing, which describes a process where an organism’s genetic code is changed, was once considered the work of science fiction. But in 2022, science fiction became reality when the use of genome editing successfully treated a teenage girl’s “incurable” cancer [1].

Alyssa was suffering from T-cell leukaemia, which is a type of cancer where the T-cells that usually defend us from disease become the disease itself, growing uncontrollably and causing immense damage. Alyssa had undergone all of the standard treatments for this type of cancer, including chemotherapy and a bone marrow transplant. However, these measures were ineffective and there was every chance that Christmas 2022 would be her last. A daunting and heart breaking possibility. Instead, she opted to try an experimental treatment involving base-edited T-cells.

These T-cells had been engineered to safely target Alyssa’s cancer without harming her, using base-editing. Remarkably, this approach showed such impressive results that in just 28 days after the treatment, Alyssa was in remission! She then went on to receive a second bone marrow transplant to restore her immune system.

This is a huge success for this treatment and paves the way for future therapeutic approaches for other diseases, potentially transforming the lives of millions of people. But how does this revolutionary technology work?

Cutting-edge technology

Every living being has a genome that contains the instructions for life. But sometimes those instructions are faulty and changes or mutations in your genetic sequence can result in a genetic disease like cancer or sickle cell disease. The human genome contains an estimated total of 20,000-25,000 genes that serve as blueprints for building all of our proteins [2]. The great majority of genetic diseases are caused by a mutation of a single base in a single gene. This means that a tool that can change a single base in a genetic sequence would be immensely powerful for treating genetic diseases.

That’s where base editors come in.

Base-editing is founded on previous genetic editing technology known as clustered regularly interspaced short palindromic repeats (CRISPR). CRISPR is a natural system found in bacteria that evolved to defend against viral infection by destroying invading DNA [3]. The CRISPR system has two main molecular components that target and cut DNA: a CRISPR-associated (Cas) enzyme that hacks the DNA and an RNA strand that guides this enzyme to a precise location in the genome.

This system is highly accurate, and thus, this mechanism for cutting DNA has been adapted by researchers into a powerful tool for genomic modification [4]. However, this approach causes double stranded breaks (DSBs) in the DNA which are repaired by the cell’s natural DNA repair system, resulting in random modifications to the gene sequence rather than a targeted base change.

Base editing is a newer genome-editing approach that uses components from CRISPR systems together with other enzymes to directly convert a target DNA base into another without creating DSBs [5]. This approach is much more targeted and controlled, making it safer and more suitable for disease treatment.

Is this the end of genetic diseases?

Millions of people worldwide have rare genetic diseases that are caused by various mutations in the DNA sequence. These disorders can have severe symptoms, and conventional therapies are frequently ineffective. However, with the advent of base editing, there is optimism that this could signal the end of genetic disease. 

Base-editing is relatively new – having only been invented six years ago – but it shows tremendous potential for the treatment of genetic disease. One study has claimed that around 60% of pathogenic point mutations could be corrected using base editors [6]. Base editing, therefore, holds the promise of a cure for a variety of illnesses, including rare diseases [7], blood disorders [8], and cancers.

The technology isn’t perfect though and there are still challenges to overcome before this type of approach will be mainstream. For example, this technology still carries a risk of base alterations into the incorrect base, extra edits within the editing window (bystander mutations), and off-target DNA editing [9]. Base-editing technologies are still in their infancy, and further characterisation of base editors in vivo is essential for enabling future therapeutic applications.

Despite these challenges, DNA base editing has already demonstrated remarkable success in correcting disease-causing mutations in mice such as Duchenne muscular dystrophy [10], sickle cell disease [8], and Hutchinson–Gilford progeria syndrome [7]. With base-editing trials already underway for the treatment of sickle-cell disease, familial high cholesterol, and beta-thalassemia, this is just the beginning of a very promising future for base-editing therapeutic applications.

While this isn’t the end of genetic disease, it heralds a new beginning for millions of people like Alyssa with rare and seemingly untreatable conditions.

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References

(1) BBC News. 2022. Base editing: Revolutionary therapy clears girl’s incurable cancer. 11 December. Available at: https://www.bbc.com/news/health-63859184 [Accessed: 2 February 2023].

(2) International Human Genome Sequencing Consortium. 2004. Finishing the euchromatic sequence of the human genome. Nature 431(7011), pp. 931–945. doi: 10.1038/nature03001.

(3) Rath, D., Amlinger, L., Rath, A. and Lundgren, M. 2015. The CRISPR-Cas immune system: Biology, mechanisms and applications. Biochimie 117, pp. 119–128. doi: 10.1016/j.biochi.2015.03.025.

(4) Cong, L. et al. 2013. Multiplex Genome Engineering Using CRISPR/Cas Systems. Science 339(6121), pp. 819–823. doi: 10.1126/science.1231143.

(5) Komor, A.C., Kim, Y.B., Packer, M.S., Zuris, J.A. and Liu, D.R. 2016. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533(7603), pp. 420–424. doi: 10.1038/nature17946.

(6) Rees, H.A. and Liu, D.R. 2018. Base editing: precision chemistry on the genome and transcriptome of living cells. Nature Reviews Genetics 19(12), pp. 770–788. doi: 10.1038/s41576-018-0059-1.

(7) Koblan, L.W. et al. 2021. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice. Nature 589(7843), pp. 608–614. doi: 10.1038/s41586-020-03086-7.

(8) Newby, G.A. et al. 2021. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature 595(7866), pp. 295–302. doi: 10.1038/s41586-021-03609-w.

(9) Jeong, Y.K., Song, B. and Bae, S. 2020. Current Status and Challenges of DNA Base Editing Tools. Molecular Therapy 28(9), pp. 1938–1952. doi: 10.1016/j.ymthe.2020.07.021.

(10) Ryu, S.-M. et al. 2018. Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. Nature Biotechnology 36(6), pp. 536–539. doi: 10.1038/nbt.4148.