Cover Letter

To: Prof. Kimberly Freeman, COLWRIT 161, College Writing Program

From: Fenmiao Zhong

Date: November 14, 2023

Subject: Demystifying Gene Therapy

This work is an “explainer” article aiming at giving a broad overview of gene therapy to the

public audience. The public audience I intend to target is people who have an interest in

understanding gene therapy in some detail but only have a basic background in biological

sciences such as knowing general biological terms like DNA, mRNA, proteins, and viruses. The

article consists of three parts. In the first part “What is gene therapy”, I give a brief explanation

of the term as well as three common types of therapy classified based on their purposes. I also

include graphic representations from BioRender.com as a supplementary explanation of the

simplified mechanisms of each type of therapy. In the second part “Applications of gene

therapy”, I give three examplary types of diseases that can be treated by gene therapy and have

been shown somewhat effective in research or clinical trials without going into extreme details.

In the third part “Caveats of gene therapy”, I give out problems and challenges of gene therapy

that need to be tackled before putting gene therapy into extensive practice. I also include the

references in APA format, the Wikipedia page and a comprehensive review article for people

with a stronger background and a stronger interest to read more. I intend to have the article

published in New Scientist which covers the latest developments in science, technology, health,

and the environment.

 Demystifying Gene Therapy

What is gene therapy?

Before delving into gene therapy, we need some background in molecular biology. The Central Dogma of
molecular biology states that genetic information flows from DNA to RNA to protein. A gene, which is a
specific segment of DNA, is transcribed into a piece of RNA. Different genes can make different types of
RNAs. Among all the RNAs made, a special type of RNAs called the messenger RNAs (mRNAs) are
translated into various proteins, which play important roles in helping people to stay healthy. If any gene
is not properly expressed at any of the DNA, RNA, or protein levels, the cells will not function normally,
and people will get diseases due to the genetic defects. Decades ago, it was hard to control gene
expression precisely since there are more than ten thousand genes in the human genome and there are
complex interactions between genes. However, with the emergence of gene therapy, people can adjust the
expression of specific genes at specific levels, aiming to produce therapeutic effects.
Many human diseases and disorders, such as cancer, cardiovascular diseases, and neurodegenerative
diseases, have been identified to have a genetic base. Gene therapy, like a high-tech toolbox, equips
people with the capability to rectify genes having mistakes to treat or cure genetic diseases. Goals or
outcomes of gene therapy involve suppression of gene expression, elevation of gene expression, or gene
correction (“Gene Therapy”, 2023).

● Suppression of Gene Expression - Shutting off the Bad Stuff

Genes can misbehave by producing too many proteins, so we need to quiet them down. A method
called RNA interference (RNAi) utilizes the function of another type of RNA fragment called
siRNA to cleave and degrade mRNA. It suppresses the hyperactive genes at the mRNA level and
reduces the production of problematic proteins. The siRNA and protein complexes required for
RNAi can be delivered into the target cell to precisely reduce the amount of specific proteins
produced by the cell.

Simplified mechanisms of RNAi (BioRender.com)

 ● Elevation of Gene Expression - Boosting the Good Stuff
Genes can also misbehave by producing too few proteins, so we need to make them more active.
Expression of a gene can be increased by directly delivering the gene as plasmid DNA into the
cell via various vehicles. The vehicles are called vectors. Depending on their composition, they
are classified as either viral (made up of viruses) or non-viral (not made up of viruses) vectors
(“Gene Therapy”, 2023). Viral vectors will introduce their genetic materials (therapeutic DNA or
mRNA) into the target host cell and the host cell will produce proteins from the therapeutic DNA
or mRNA. Commonly used viral vectors include lentiviral vectors, adenoviral vectors, and
adeno-associated viral vectors (AAVs) (“Gene Therapy”, 2023). Non-viral vectors utilize organic
materials to package and deliver therapeutic genes into the target cells. Common methods include
liposomes, dendrimers, and nanoparticles (“Gene Therapy”, 2023).

● Gene correction - Fixing Genetic Typos

Genes are not always correct. Typos can present when genetic information is passed down over
generations, and we need to correct those typos by bringing in the editors – nucleases. Nucleases
are enzymes that induce a cut in the genome, which can be repaired erroneously, or faithfully if a
repair template is given. By using engineered nucleases that can be directed to specific places in
the genome to perform cutting, the corrective gene therapy can fix the mistakes in the genome.
Commonly used editors include zinc-finger nucleases (ZFNs), transcription activator-like effector
nucleases (TALENs), and clustered regulatory interspaced short tandem repeats (CRISPR)
/CRISPR associated protein (Cas) (Sayed et al., 2022).

Simplified mechanisms of ZFNs, TALENs, and CRISPR/Cas in gene therapy (BioRender.com)

Applications of gene therapy

Gene therapy has the potential to mitigate inherited and acquired genetic diseases. Clinical trials have put
gene therapy into practice for treating complex diseases such as cancers, cardiovascular diseases, and
neurodegenerative diseases (Sayed et al., 2022).
 ● Cancer - Fighting against the Devils
Gene therapy shows promise in cancer treatment. For example, in many cancer models, such as
lung cancer, pancreatic cancer, and liver cancer, gene therapy can generate vaccines by targeting
viruses to kill cancer cells or delivering genes to cancer cells to convert them back to normal.
Those vaccines arm people’s defense systems with specialized weapons to fight against the
rampant cancer cells. To generate cancer vaccines, the patient’s cancer cells are harvested to grow
and some genes will be inserted into the cells to stimulate immune responses. The modified cells
are then killed and the released components are assembled into vaccines.

● Cardiovascular disease - Fixing Broken Hearts

Gene therapy serves as a novel alternative treatment for cardiovascular disease. For example, in
heart diseases, gene therapy allows the substitution of a defective copy of a gene for a normal
copy of a gene. Vectors carrying the desired genes are introduced by injection into the
bloodstream. Gene therapy is considered to have lower toxicity compared to drugs and is less
likely to cause additional diseases. It is like upgrading the heart software without the side effects
of traditional drugs.

● Neurodegenerative disease - Restoring Brain Power

Gene therapy benefits people with neurodegenerative diseases, such as Alzheimer’s disease and
Parkinson’s disease, where problematic proteins are mistakenly produced. Functional genes of
interest can be transferred into the brain to restore the functions of neurons, control the symptoms,
or correct the pathogenic mechanisms.

In addition to the diseases described above, gene therapy has been shown to play an effective role in
treating many infectious diseases and inherited diseases using different strategies (Sayed et al., 2022).

Caveats of gene therapy

Despite the power of gene therapy to treat and cure diseases, it is still in the early developmental stages
and there are many ongoing problems to be tackled (“Gene Therapy”, 2023):

● Immune response
When gene therapy introduces a foreign piece of gene into human cells, the immune system will
be activated to recognize the foreign object and attack it. Enhanced immune response will result
in unexpected adverse symptoms and reduced effectiveness of following treatments.

● Short-lived characteristics
The genes conferring therapeutic effects that are introduced into the targeted cells need to remain
functional and the targeted cells with therapeutic genes incorporated into need to remain stable.
To retain the effects over generations, the therapeutic genes need to be integrated into the nuclear
genome and dividing cells, but getting foreign genes into the nucleus is still a challenge and
dividing cells can undergo many changes during the development, reducing the duration of
effects.

● Mutagenic Effects
 If the therapeutic genes are integrated in an unexpected spot in the genome or a sensitive spot, the
therapy can induce undesirable mutations in the genome and disrupt the normal functionality of
the native genes. The vectors for delivering genes, such as viruses, have risks of being toxic to the
cells, inducing immune responses, and causing non-intended mutations in the genome.

● Cost
The gene therapy is usually customized for each patient and it takes great time and money to
design a personalized way to deliver therapeutic genes into the patient’s cells to cure a specific
disease. The cost can even reach the price of a million per patient, rendering it the most expensive
type of drug.

Conclusion
Gene therapy is a groundbreaking adventure in medicine, with revolutionary therapeutic potential. Just
like any superhero, it has its own challenges. As science progresses, we can hopefully expect more
improvements in gene therapy to enhance its effectiveness and reduce its side effects.

References:
1.Sayed, N., Allawadhi, P., Khurana, A., Singh, V., Navik, U., Pasumarthi, S. K., Khurana, I., Banothu, A.
K., Weiskirchen, R., & Bharani, K. K. (2022). Gene therapy: Comprehensive overview and therapeutic
applications. Life sciences, 294, 120375. https://doi.org/10.1016/j.lfs.2022.120375
2.Wikipedia contributors. Gene therapy. Wikipedia, The Free Encyclopedia. Updated November 12, 2023.
Accessed November 13, 2023. https://en.wikipedia.org/wiki/Gene_therapy