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Help Me Understand Genetics

Gene Therapy and Other Medical Advances

Reprinted from MedlinePlus Genetics

U.S. National Library of Medicine

National Institutes of Health

Department of Health & Human Services


CONTENTS

1 What is gene therapy? 1

2 How does gene therapy work? 3

3 Is gene therapy safe? 6

4 What are the ethical issues surrounding gene therapy? 8

5 Is gene therapy available to treat my disorder? 9

6 What are CAR T cell therapy, RNA therapy, and other genetic
therapies? 9
7 What are mRNA vaccines and how do they work? 11

Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/)


Gene Therapy and Other Medical Advances

1 What is gene therapy?

Gene therapy is a medical approach that treats or prevents disease by


correcting the underlying genetic problem. Gene therapy techniques
allow doctors to treat a disorder by altering a person’s genetic makeup
instead of using drugs or surgery.
The earliest method of gene therapy, often called gene transfer or gene
addition, was developed to:
• Introduce a new gene into cells to help fight a disease.
• Introduce a non-faulty copy of a gene to stand in for the altered copy
causing disease.
Later studies led to advances in gene therapy techniques. A newer
technique, called genome editing (an example of which is CRISPR-Cas9),
uses a different approach to correct genetic differences. Instead of
introducing new genetic material into cells, genome editing introduces
molecular tools to change the existing DNA in the cell. Genome editing is
being studied to:
• Fix a genetic alteration underlying a disorder, so the gene can function
properly.
• Turn on a gene to help fight a disease.
• Turn off a gene that is functioning improperly.
• Remove a piece of DNA that is impairing gene function and causing
disease.
Gene therapies are being used to treat a small number of diseases,
including an eye disorder called Leber congenital amaurosis and a
muscle disorder called spinal muscular atrophy. Many more gene
therapies are undergoing research to make sure that they will be safe and
effective. Genome editing is a promising technique also under study that
doctors hope to use soon to treat disorders in people.

For general information about gene therapy:

MedlinePlus offers a list of links to information about genes and gene


therapy (https://m edlineplus.gov/genesandgenetherapy.html).
The Genetic Science Learning Center at the University of Utah provides
an interactive introduction to gene therapy
(https://learn.genetics.utah.edu/content/genetherapy/) and a discussion of
several diseases for which gene therapy has been successful (https://le
arn.genetics.utah.edu/content/genetherapy/success/).
The Centre for Genetics Education provides an introduction to gene therapy
and other therapeutics (https://www.genetics.edu.au/SitePages/Gene-
therapy-advanced-therapeu tics.aspx), including a discussion of ethical and
safety considerations.
The National Heart, Lung, and Blood Institute describes the approaches to
gene therapy and how they work (https://www.nhlbi.nih.gov/health-
topics/genetic-therapies).
Your Genome from the Wellcome Genome Campus provides an
introduction to gene therapy and describes several techniques
(https://www.yourgenome.org/facts/what-is-g ene-therapy).
KidsHealth from Nemours offers a fact sheet called Gene Therapy and
Children (https:// kidshealth.org/en/parents/gene-therapy.html).
2 How does gene therapy work?

Gene therapy works by altering the genetic code to recover the functions
of critical proteins. Proteins are the workhorses of the cell and the
structural basis of the body’s tissues. The instructions for making proteins
are carried in a person’s genetic code, and variants (or mutations) in this
code can impact the production or function of proteins that may be critical
to how the body works. Fixing or compensating for disease-causing
genetic changes may recover the role of these important proteins and
allow the body to function as expected.
Gene therapy can compensate for genetic alterations in a couple different
ways.
• Gene transfer therapy introduces new genetic material into cells. If an
altered gene causes a necessary protein to be faulty or missing, gene
transfer therapy can introduce a normal copy of the gene to recover
the function of the protein.
Alternatively, the therapy can introduce a different gene that provides
instructions for a protein that helps the cell function normally, despite
the genetic alteration.
• Genome editing is a newer technique that may potentially be used for
gene therapy. Instead of adding new genetic material, genome editing
introduces gene-editing tools that can change the existing DNA in the
cell. Genome editing technologies allow genetic material to be added,
removed, or altered at precise locations in the genome. CRISPR-Cas9
is a well-known type of genome editing.
Genetic material or gene-editing tools that are inserted directly into a cell
usually do not function. Instead, a carrier called a vector is genetically
engineered to carry and deliver the material. Certain viruses are used as
vectors because they can deliver the material by infecting the cell. The
viruses are modified so they can't cause disease when used in people.
Some types of virus, such as retroviruses, integrate their genetic material
(including the new gene) into a chromosome in the human cell. Other
viruses, such as adenoviruses, introduce their DNA into the nucleus of the
cell, but the DNA is not integrated into a chromosome. Viruses can also
deliver the gene-editing tools to the nucleus of the cell.
The vector can be injected or given intravenously (by IV) directly into a
specific tissue in the body, where it is taken up by individual cells.
Alternately, a sample of the patient's cells can be removed and exposed
to the vector in a laboratory setting. The cells containing the vector are
then returned to the patient. If the treatment is successful, the new gene
delivered by the vector will make a functioning protein or the editing
molecules will correct a DNA error and restore protein function.
Gene therapy with viral vectors has been successful, but it does carry
some risk. Sometimes the virus triggers a dangerous immune response. In
addition, vectors that integrate the genetic material into a chromosome
can cause errors that lead to cancer. Researchers are developing newer
technologies that can deliver genetic material or gene-editing tools
without using viruses. One such technique uses special structures called
nanoparticles as vectors to deliver the genetic material or gene-editing
components into cells. Nanoparticles are incredibly small structures that
have been developed for many uses. For gene therapy, these tiny particles
are designed with specific characteristics to target them to particular cell
types. Nanoparticles are less likely to cause immune reactions than viral
vectors, and they are easier to design and modify for specific purposes.
Researchers continue to work to overcome the many technical challenges
of gene therapy. For example, scientists are finding better ways to deliver
genes or gene-editing tools and target them to particular cells. They are also
working to more precisely control when the treatment is functional in the
body.

Scientific journal articles for further reading

Bulcha JT, Wang Y, Ma H, Tai PWL, Gao G. Viral vector platforms


within the gene therapy landscape. Signal Transduct Target Ther. 2021
Feb 8;6(1):53. doi: 10.1038/ s41392-021-00487-6. PMID: 33558455. Free
full-text article from PubMed Central: PMC7868676.
Duan L, Ouyang K, Xu X, Xu L, Wen C, Zhou X, Qin Z, Xu Z, Sun W,
Liang Y.
Nanoparticle Delivery of CRISPR/Cas9 for Genome Editing. Front Genet.
2021 May 12; 12:673286. doi: 10.3389/fgene.2021.673286. PubMed:
34054927. Free full-text article from PubMed Central: PMC8149999.

A new gene is inserted directly into a cell. A carrier called a vector is


genetically engineered to deliver the gene. An adenovirus introduces the
DNA into the nucleus of the cell, but the DNA is not integrated into a
chromosome. ( Figure 1)

FIGURE 1: A new gene is inserted directly into a cell. A


carrier called a vector is genetically engineered to deliver
the gene. An adenovirus introduces the DNA into the
nucleus of the cell, but the DNA is not integrated into a
chromosome.
For more information about how gene therapy works:

Boston Children’s Hospital summarizes the evolution of gene therapy


techniques (https: //answers.childrenshospital.org/gene-therapy-history/).
The Genetic Science Learning Center at the University of Utah provides
information about various technical aspects of gene therapy in Gene
Delivery: Tools of the Trade (ht
tps://learn.genetics.utah.edu/content/genetherapy/tools/). They also
discuss other approaches to gene therapy
(https://learn.genetics.utah.edu/content/genetherapy/appro aches/) and
offer a related learning activity called Space Doctor
(https://learn.genetics.u tah.edu/content/genetherapy/doctor/).
The American Society of Gene and Cell Therapy offers an in-depth
description of the different types of viral vectors used in gene therapy
(https://patienteducation.asgct.org/g ene-therapy-101/vectors-101).
Penn Medicine's OncoLink describes how gene therapy works and how it
is administered to patients
(https://www.oncolink.org/cancer-treatment/immunotherapy/wh at-is-
gene-therapy).
The basics of nanoparticles and their use in medicine
(https://askabiologist.asu.edu/tinymedicine) are explained in the Ask a
Biologist feature from Arizona State University.
Your Genome from the Wellcome Genome campus explains the first
gene therapy trial to treat a condition called severe combined
immunodeficiency (SCID) (https://www.your
genome.org/stories/treating-the-bubble-babies-gene-therapy-in-use). It
also describes other applications for gene therapy.
3 Is gene therapy safe?

The first gene therapy trial was run more than thirty years ago. The
earliest studies showed that gene therapy could have very serious health
risks, such as toxicity, inflammation, and cancer. Since then, researchers
have studied the mechanisms and developed improved techniques that are
less likely to cause dangerous immune reactions or cancer. Because gene
therapy techniques are relatively new, some risks may be unpredictable;
however, medical researchers, institutions, and regulatory agencies are
working to ensure that gene therapy research, clinical trials, and approved
treatments are as safe as possible.
Comprehensive federal laws, regulations, and guidelines help protect
people who participate in research studies (called clinical trials). The U.S.
Food and Drug Administration (FDA) regulates all gene therapy products
in the United States and overseas research in this area. Researchers who
wish to test an approach in a clinical trial must first obtain permission
from the FDA. The FDA has the authority to reject or suspend clinical
trials that are suspected of being unsafe for participants.
The National Institutes of Health (NIH) also plays an important role in
ensuring the safety of gene therapy research. NIH provides guidelines for
investigators and institutions (such as universities and hospitals) to
follow when conducting clinical trials with gene therapy. These
guidelines state that clinical trials at institutions receiving NIH funding
for this type of research must be registered with the NIH Office of
Biotechnology Activities. The protocol, or plan, for each clinical trial is
then reviewed by the NIH
Recombinant DNA Advisory Committee (RAC) to determine whether it
raises medical, ethical, or safety issues that warrant further discussion at a
RAC public meeting.
An Institutional Review Board (IRB) and an Institutional Biosafety
Committee (IBC) must approve each gene therapy clinical trial before it
can be carried out. An IRB is a committee of scientific and medical
advisors and consumers that reviews all research within an institution. An
IBC is a group that reviews and approves an institution's potentially
hazardous research studies. Multiple levels of evaluation and oversight
ensure that safety concerns are a top priority in the planning and carrying
out of gene therapy research.
The clinical trial process occurs in three phases. Phase I studies
determine if a treatment is safe for people and identify its side effects.
Phase II studies determine if the treatment is effective, meaning whether
it works. Phase III studies compare the new treatment to the current
treatments available. Doctors want to know whether the new treatment
works better or has fewer side effects than the standard treatment. The
FDA reviews the results of the clinical trial. If it determines that the
benefits of the new treatment outweigh the side effects, it approves the
therapy, and doctors can use it to treat a disorder.
Successful clinical trials have led to the approval of a small number of gene
therapies, including therapies to treat inherited disorders like spinal
muscular atrophy and Leber congenital amaurosis.
For more information about the safety and oversight of gene therapy:

The Genetic Science Learning Center at the University of Utah explains


challenges related to gene therapy
(https://learn.genetics.utah.edu/content/genetherapy/challenges
/).
The NIH's Office of Biotechnology Activities provides NIH guidelines for
biosafety (https:
//osp.od.nih.gov/biotechnology/nih-guidelines/).
4 What are the ethical issues surrounding gene therapy?

Because gene therapy involves making changes to the body’s basic


building blocks (DNA), it raises many unique ethical concerns. The ethical
questions surrounding gene therapy and genome editing include:
• How can “good” and “bad” uses of these technologies be distinguished?
• Who decides which traits are normal and which constitute a disability or
disorder?
• Will the high costs of gene therapy make it available only to the
wealthy?
• Could the widespread use of gene therapy make society less accepting of
people who are different?
• Should people be allowed to use gene therapy to enhance basic human
traits such as height, intelligence, or athletic ability?
Current research on gene therapy treatment has focused on targeting body
(somatic) cells such as bone marrow or blood cells. This type of genetic
alteration cannot be passed to a person’s children. Gene therapy could be
targeted to egg and sperm cells (germ cells), however, which would allow
the genetic changes to be passed to future generations. This approach is
known as germline gene therapy.
The idea of these germline alterations is controversial. While it could
spare future generations in a family from having a particular genetic
disorder, it might affect the development of a fetus in unexpected ways
or have long-term side effects that are not yet known. Because people
who would be affected by germline gene therapy are not yet born, they
can’t choose whether to have the treatment. Because of these ethical
concerns, the U.S. Government does not allow federal funds to be used
for research on germline gene therapy in people.

For more information about the ethical issues raised by gene therapy:
The National Human Genome Research Institute discusses the ethical
concerns of genome editing
(https://www.genome.gov/about-genomics/policy-issues/Genome-Editin
g/ethical-concerns).
A debate of the ethics of germline gene therapy (
https://www.yourgenome.org/debates/i s-germline-gene-therapy-ethical) is
presented by yourgenome.org from the Wellcome Genome Campus.
A discussion of the ethics of gene therapy and genetic engineering
(https://medicine.mis
souri.edu/centers-institutes-labs/health-ethics/faq/gene-therapy) is available
from the University of Missouri Center for Health Ethics.
5 Is gene therapy available to treat my disorder?

Gene therapy is currently available primarily in a research setting. The


U.S. Food and Drug Administration (FDA) has approved only a small
number of gene therapy products for sale in the United States. For
example, FDA-approved gene therapies are available for conditions that
include a rare eye disorder called Leber congenital amaurosis, a form of
skin cancer known as melanoma, and a genetic muscle condition called
spinal muscular atrophy. Other genetic therapies have been approved for
blood cell cancers such as lymphoma and multiple myeloma. Gene
therapies to treat additional conditions have been approved in other
countries.
Hundreds of research studies (clinical trials) are under way to test gene
therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If
you are interested in participating in a clinical trial, talk with your doctor
or a genetics professional about how to participate.

For information about gene therapy clinical trials:

You can also search for clinical trials online. ClinicalTrials.gov


(https://clinicaltrials.gov/), a service of the National Institutes of Health,
provides easy access to information about clinical trials. You can search
for a specific clinical trial or browse by health condition or sponsor. You
may wish to refer to a list of gene therapy clinical trials
(https://clinicaltrials .gov/search?term=%22gene+therapy%22) or gene or
genome editing clinical trials (http s://clinicaltrials.gov/ct2/results?
cond=&term=%22gene+editing%22+OR+%22geno me+editing
%22) that are accepting (or will accept) participants.
An explanation of the clinical trial process and how to find a clinical trial
is presented by the American Society of Gene and Cell Therapy
(https://patienteducation.asgct.org/gen e-therapy-101/clinical-trials-
process).
6 What are CAR T cell therapy, RNA therapy, and other genetic
therapies?

Several treatments have been developed that involve genetic material but
are typically not considered gene therapy. Some of these methods alter
DNA for a slightly different use than gene therapy. Others do not alter
genes themselves, but they change whether or how a gene’s instructions
are carried out to make proteins.
Cell-based gene therapy
CAR T cell therapy (or chimeric antigen receptor T cell therapy) is an
example of cellbased gene therapy. This type of treatment combines the
technologies of gene therapy and cell therapy. Cell therapy introduces
cells to the body that have a particular function to help treat a disease. In
cell-based gene therapy, the cells have been genetically altered to give
them the special function. CAR T cell therapy introduces a gene to a
person’s T cells, which are a type of immune cell. This gene provides
instructions for making a protein, called the chimeric antigen receptor
(CAR), that attaches to cancer cells. The modified immune cells can
specifically attack cancer cells.
RNA therapy
Several techniques, called RNA therapies, use pieces of RNA, which is a
type of genetic material similar to DNA, to help treat a disorder. In many
of these techniques, the pieces of RNA interact with a molecule called
messenger RNA (or mRNA for short). In cells, mRNA uses the
information in genes to create a blueprint for making proteins. By
interacting with mRNA, these therapies influence how much protein is
produced from a gene, which can compensate for the effects of a genetic
alteration. Examples of these RNA therapies include antisense
oligonucleotide (ASO), small interfering RNA (siRNA), and microRNA
(miRNA) therapies. An RNA therapy called RNA aptamer therapy
introduces small pieces of RNA that attach directly to proteins to alter
their function.
Epigenetic therapy
Another gene-related therapy, called epigenetic therapy, affects
epigenetic changes in cells. Epigenetic changes are specific
modifications (often called “tags”) attached to DNA that control whether
genes are turned on or off. Abnormal patterns of epigenetic
modifications alter gene activity and, subsequently, protein production.
Epigenetic therapies are used to correct epigenetic errors that underlie
genetic disorders.

Scientific journal articles for further reading

Kim YK. RNA Therapy: Current Status and Future Potential. Chonnam
Med J. 2020 May;56(2):87-93. doi: 10.4068/cmj.2020.56.2.87. Epub 2020
May 25. PubMed: 32509554. Free full-text article from PubMed Central:
PMC7250668.
Lu Y, Chan YT, Tan HY, Li S, Wang N, Feng Y. Epigenetic regulation in
human cancer: the potential role of epi-drug in cancer therapy. Mol Cancer.
2020 Apr 27;19(1):79. doi:
10.1186/s12943-020-01197-3. 32340605. Free full-text article from
PubMed Central:
PMC7184703.
7 What are mRNA vaccines and how do they work?

Vaccines help prevent infection by preparing the body to fight foreign


invaders (such as bacteria, viruses, or other pathogens). All vaccines
introduce into the body a harmless piece of a particular bacteria or virus,
triggering an immune response. Most vaccines contain a weakened or
dead bacteria or virus. However, scientists have developed a new type of
vaccine that uses a molecule called messenger RNA (mRNA) rather than
part of an actual bacteria or virus. Messenger RNA is a type of RNA that
is necessary for protein production. Once cells finish making a protein,
they quickly break down the mRNA. mRNA from vaccines does not
enter the nucleus and does not alter DNA.
mRNA vaccines work by introducing a piece of mRNA that corresponds
to a viral protein, usually a small piece of a protein found on the virus’s
outer membrane. (Individuals who get an mRNA vaccine are not
exposed to the virus, nor can they become infected with the virus by the
vaccine.) By using this mRNA, cells can produce the viral protein. As
part of a normal immune response, the immune system recognizes that
the protein is foreign and produces specialized proteins called antibodies.
Antibodies help protect the body against infection by recognizing
individual viruses or other pathogens, attaching to them, and marking the
pathogens for destruction. Once produced, antibodies remain in the body,
even after the body has rid itself of the pathogen, so that the immune
system can quickly respond if exposed again. If a person is exposed to a
virus after receiving mRNA vaccination for it, antibodies can quickly
recognize it, attach to it, and mark it for destruction before it can cause
serious illness.
Like all vaccines in the United States, mRNA vaccines require
authorization or approval from the Food and Drug Administration (FDA)
before they can be used. Currently vaccines for COVID-19, the disease
caused by the SARS-CoV-2 coronavirus, are the only authorized or
approved mRNA vaccines. These vaccines use mRNA that directs cells
to produce copies of a protein on the outside of the coronavirus known as
the “ spike protein”. Researchers are studying how mRNA might be used
to develop vaccines for additional diseases.

Scientific journal articles for further reading

Jain S, Venkataraman A, Wechsler ME, Peppas NA. Messenger RNA-


based vaccines:
Past, present, and future directions in the context of the COVID-19
pandemic. Adv Drug Deliv Rev. 2021 Oct 9;179:114000. doi:
10.1016/j.addr.2021.114000. Epub ahead of print. PMID: 34637846;
PMCID: PMC8502079.
Verbeke R, Lentacker I, De Smedt SC, Dewitte H. The dawn of mRNA
vaccines: The COVID-19 case. J Control Release. 2021 May 10; 333:511-
520. Doi: 10.1016/j.jconrel. 2021.03.043. Epub 2021 Mar 30. PMID:
33798667; PMCID: PMC8008785.

Microscopic image of SARS-CoV-2, the virus that causes COVID-19.


Spike proteins are seen surrounding the outer membrane of each virus
particle. ( Figure 2)
FIGURE 2: Microscopic image of four SARS-CoV-2
virus particles, the virus that causes COVID-19. Spike
proteins are seen surrounding the outer membrane of
each virus particle.

For more information about mRNA vaccines:

MedlinePlus offers many additional resources with information about


mRNA vaccines, specifically relating to their use in COVID-19
• MedlinePlus: Health Topic: COVID-19 Vaccines
(https://medlineplus.gov/covid19va ccines.html)
• MedlinePlus: Encyclopedia: COVID-19 vaccines
(https://medlineplus.gov/ency/articl e/007775.htm)
• MedlinePlus: Drugs and Supplements: COVID-19 Vaccine, mRNA
(Pfizer-BioNTech)
(https://medlineplus.gov/druginfo/meds/a621003.html)
• MedlinePlus: Drugs and Supplements: COVID-19 Vaccine, mRNA
(Moderna) (https : //medlineplus.gov/druginfo/meds/a621002.html )
The National Institute of Allergy and Infectious Diseases provides in-
depth information
(https://www.niaid.nih.gov/diseases-conditions/coronavirus-vaccines-
prevention) about the COVID-19 vaccines.
The Centers for Disease Control and Prevention has a fact sheet
(https://www.cdc.gov/c oronavirus/2019-ncov/vaccines/different-
vaccines/mRNA.html) on mRNA vaccines.

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