Rewriting Illness: Cure for genetic disorders, now possible with genome editing

By Karl Andrei Luarez

PHOTO: Adobe Stock 

A report published by Aymé, S. showed that three in 50,000 people at some point in their life contract a monogenic disease which is caused by point mutations, which happens when a single base pair is added, deleted, or changed from a DNA at some point in their life. Although point mutations happen in the cell frequently it is in most cases benign and the probability of a point mutation resulting in a monogenic disease is unlikely.

However, there are occasions when the genetic error may cause a cell to behave abnormally and disrupt its normal function which can lead to monogenic diseases. Despite their rarity, thousands of people still suffer from monogenic illnesses such as progeria (genetic disorder that causes children to age rapidly) and Tay-Sachs disease (genetic sickness that causes the absence of an enzyme that helps break down fatty substances), which has no known cure.

As more advancements in genetic engineering spews forth, treating monogenic illnesses is now a possibility through genome editing. Although this may seem like science fiction, David Liu, a professor of chemistry and chemical biology and director of the Merkin Institute of Transformative Technologies in Healthcare, and his team are now in the works in developing a new gene editing technology – CRISPR 2.0 base editing.

Rewriting our DNA
    
 One of the most common forms of modern-day gene editing is CRISPR, which works through a protein CRISPR-Cas9 which snips a specific DNA sequence using molecular scissors. On a TED Talk, Liu explained that the way CRISPR works today is impractical in therapeutic genome editing, specially in monogenic diseases, since only cutting a sequence of a gene disrupts and does not restore its proper function.  
 
Our DNA is equipped with four bases: adenine (A), cytosine (C), guanine (G), and thymine (T); which form specific pairs: A with T, and G with C. In children with progeria, they are born with a T in a position in their genome where there is usually a C; to fix this the progeria causing base T should be replaced with a C.

Think of DNA as a tower of building blocks in which a block represents a single base and to make sure that the tower is structurally sound, it has to follow a specific sequence. Adding a large block where there should be a small one could put the tower’s integrity at risk and could cause it to topple over (which is what a mutation and disease would be). If it is fixed the way CRISPR works by taking out a sequence of blocks, it would result in a shorter tower or a collapse of the top portion, 

Hence Liu transforms the way CRISPR works and programs it to repair abnormal sequences through molecular machines he calls “base editors.” They work by accurately changing the misspelled base into another without causing a break in the sequence through precisely binding to the DNA and accurately rearranging the atoms to convert it to the correct base. 

In children with progeria, they are born with a T in a position in their genome where there is usually a C; to fix this using base editing the progeria causing base T should be converted to a C.

Now, the tower can be repaired by simply replacing the erroneous block with the correct one.

Molecular Machines

Liu explained that unlike CRISPR, base editing is not a naturally occurring mechanism found in nature. And to make this marvel work, they had to engineer their first gene editor from three different proteins from different organisms.

WATCH: “Can we cure genetic diseases by rewriting DNA? | David Liu”

They started with using CRISPR-Cas9 and modified it such that it could not break DNA but could still detect its target genetic sequence and bind accurately. Next, they attached a protein which undergoes a chemical process in the base C to convert it to a base that resembles T. Then, they attached a third protein which protects the now converted base T from being removed by the cell.

After this milestone, Liu still feels that their work not yet complete, because DNA must make correct base pairings in cells in order for it to be stable: A with T and G with C. Replacing the G-paired C would cause a mismatch with the newly placed base T in which the has to fix by deciding which strand to replace. Thus, Liu and his team reprogrammed the base editor protein to make sure that the non-edited strand gets replaced by nicking and damaging it which tricks the cell into replacing the non-edited G with an A.

The future of base editing
    
One of the goals of this technology is to integrate it to treat point mutation-caused diseases in humans. However, the journey is still very long since base editors are still too young for human clinical trials. Scientists are now working towards that goal with the start of trials on animals such as mice to correct point mutations that cause monogenic diseases via base editing.
    
Liu shared that his students Luke Koblan and Jon Levy successfully cured a mouse with progeria using a virus to deliver a base editor and change the progeria-causing base T to a C. He also mentioned that base editing has also been used in animals to treat diseases such as tyrosinemia, muscular dystrophy, congenital deafness, and phenylketonuria through correcting a point mutation.

Base editing can also be utilized in agriculture, with success in plants equipped with base editors that change specific DNA bases which could bolster its growth, leading to better crops. 

Researchers are also looking into the possibility of treating cancer with base editing, given the disease’s usual origin from point mutations. A paper by Martin In a study by Martin Pal and Marco Herold, "high potential" was expressed for the use of base editors in tumor modeling, therapeutic editing, or functional screening.
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