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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
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.
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:
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?
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.
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?