This site is an educational service brought to you by BioMarin and is intended for US residents only. Many gene therapies for hemophilia A and B are being studied in people to determine if they are safe and effective. No gene therapies for hemophilia have been approved for use or determined to be safe or effective.
01
What is a gene?

Let's take a closer look at the instruction manual for the human body

You’ve probably heard about genes and how you got your hair color from one biological parent and your eye color from the other. But there is so much more to genetics and how genes work in the body.

GENES ARE SEGMENTS OF DNA

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The key role of genes is to provide the instructions for making proteins. Proteins are the building blocks of the body and serve important functions like tissue repair and helping blood to clot.

GENES ARE SEGMENTS OF DNA

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Think of DNA as the language used in your genetic instructions. DNA is made up of components called nucleotide bases that are like the letters of a word. You must have the correct nucleotide bases in the correct order for the gene to fulfill its intended purpose—producing proteins with normal function.

DNA stands for deoxyribonucleic acid. The 4 nucleotide bases responsible for gene construction are adenine (A), guanine (G), cytosine (C), and thymine (T). These nucleotides pair up with each other, A with T and C with G.

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A chromosome

They can be found in our chromosomes, which contain tens of thousands of known genes. Your chromosomes lie deep within a structure called the nucleus, which acts as the command center of the cells that make up your body.

Human cells typically contain 23 pairs of chromosomes. In males and females, 22 of those pairs look the same. The 23rd pair, also called the sex chromosomes, differs between males and females. Females have two copies of the X chromosome while males have a single pair of X and Y chromosomes.

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02
What causes
genetic conditions?

A mutation, or variation, in just one gene can cause a genetic condition

Did you know there are approximately 20,000 genes in the human genome? A mutation, or permanent variation, in just one gene can lead to a genetic condition. Knowing what causes a genetic condition is the first step in understanding how, potentially through ongoing research in gene therapy, physicians might be able to treat these conditions differently.

GENETIC CONDITIONS ARE THE RESULT OF MUTATIONS

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Genetic conditions are the result of mutations, or variations, in the structure of a gene. These mutations are most often passed down from biological parents but can sometimes happen spontaneously. Cystic fibrosis and hemophilia are examples of genetic conditions.

In hemophilia A, the gene responsible for producing factor VIII is mutated. This gene is located in the X chromosome. Males have only one X chromosome, which means that one copy of the mutated gene is enough to cause hemophilia, making it more common in this population.

While it is rare, females with just one affected chromosome can sometimes show symptoms of hemophilia. But because females have two X chromosomes, both chromosomes would need to have a mutation for them to be severely affected by the disease. However, females who do not show signs of hemophilia are often referred to as "carriers" because they can still pass on the mutated gene to their children, even though they have no symptoms of the condition.

MUTATIONS CAN AFFECT YOUR GENETIC INSTRUCTIONS

A mutation can affect the genetic instructions in your body. The instructions can be missing or incorrect, changing the way proteins are produced. This can result in the production of a protein that does not work properly or, in some cases, the protein is not produced at all.

Mutations can take the form of changed nucleotide pairings, extra DNA where it doesn’t belong, missing DNA, or repeated DNA.

In people with hemophilia A or B, the genetic mutation affects the body’s ability to produce a protein called factor VIII or factor IX, respectively. These proteins are critical for blood to clot.

THERE ARE 3 TYPES OF GENETIC CONDITIONS

The 3 types of genetic conditions are single-gene conditions, multi-gene conditions, and chromosomal conditions.

  • Monogenic conditions—like hemophilia—are caused by a mutation in a single gene. Other examples include cystic fibrosis and Huntington disease
  • Multifactorial inheritance conditions, or multi-gene conditions, develop from multiple small genetic mutations and can lead to some of the more common diseases we’re familiar with, such as heart disease and diabetes
  • Chromosome disorders are caused by changes to the number or structure of chromosomes. Down syndrome is the most common disorder related to this type of abnormality

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03
What is gene
therapy?

A possible solution to genetic conditions being evaluated in multiple clinical trials for a range of genetic conditions to determine the risks and benefits

A genetic condition could potentially have a genetic solution, right? This logical thinking gave birth to the first research in gene therapy more than 50 years ago. Now being evaluated in multiple clinical trials for a range of genetic conditions to determine the possible benefits and risks, gene therapy research has the potential to bring an entirely new option to people with specific genetic conditions and those who support and care for them.

GENE THERAPY SEEKS TO ADDRESS GENETIC MUTATIONS

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Inside a cell

Simply put, gene therapy is being researched in clinical studies as a novel method that attempts to use genes to treat or prevent disease.

METHODS OF GENE THERAPY BEING EXPLORED

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Gene transfer therapy

A few different approaches to gene therapy are being explored. Gene therapy may involve attempting to repair or replace a mutated gene, disabling a mutated gene that is causing trouble, or introducing a functional copy of the gene into the body to help the body produce the affected protein.

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Ex vivo gene therapy

  • With the method of gene therapy called gene transfer, a functional gene is inserted into a cell with the intent that it will work in place of the mutated gene. Viral, chemical, and physical methods are being explored for transferring genes. The transfer of the new gene occurs inside the body (in vivo) after systemic delivery, often using an IV infusion. The original genetic material in the chromosomes is intended to be left unchanged. This means the mutated gene would still be there and can still be passed on to a person’s offspring
  • In ex vivo gene therapy, a type of cell-based therapy, the process happens outside the body. First, affected cells are removed from the body via a biopsy. In the lab, functional genetic material is introduced into the cells and are then delivered back into the patient’s body
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Gene editing

  • In gene editing, the idea is to make changes to the original DNA. This technique makes it possible to repair the original DNA or add new DNA in a specific location. Zinc finger nucleases and CRISPR (clustered regularly interspaced short palindromic repeats) are methods of gene editing being researched

50+ YEARS OF RESEARCH

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Gene therapy has been explored as a potential treatment approach for well over 50 years. In the past decade, the FDA and EMA (European Medicines Agency) have approved gene therapies for genetic conditions. Gene therapy is currently being researched in many clinical trials for various genetic disorders, including hemophilia A and B and has not been determined to be safe or effective.

To explore future, current, and past research in gene therapy, visit ClinicalTrials.gov

GENE THERAPY TIMELINE

1972 —Concept of gene therapy considered as a form of treatment in the journal Science
1984 —Dr. Gordon Vehar publishes a paper reporting successful factor VIII cloning
1990 —First gene therapy trial in humans
1999 —Lessons learned regarding risks related to potential for severe immune response in early gene therapy trial with non-adeno-associated virus (AAV) vector
2003 —The Human Genome Project is completed
2003 —China approves the first gene therapy for the treatment of head and neck cancers
2005 —First gene therapy trial in hemophilia B using AAV vector technology
2015 —First gene therapy trial in hemophilia A using AAV vector technology
2017 —The first gene therapy, for a genetic disease that causes blindness, is approved in the United States
Future —Additional gene therapies are being researched

ONGOING RESEARCH

Gene therapy is in ongoing clinical trial research to determine the potential risks and benefits of treatment.

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04
How is gene therapy
designed to work?

Ongoing research is investigating a different approach to the way we've managed genetic conditions

It's not magic—it's science in progress. Many gene therapies are under investigation and some have been approved for use for conditions other than hemophilia A or B. The risks and benefits of each gene therapy is evaluated independently and if a clinical trial for a particular gene therapy is successful, it has the potential to offer a remarkably different approach to the way we've historically managed genetic disease. Let's look at an example…

GENE TRANSFER

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Gene transfer therapy

Currently undergoing clinical trials in many different conditions, including hemophilia A and B, this method of gene therapy aims to introduce a functioning gene that can instruct the body to produce the needed protein.

CREATING A FUNCTIONAL GENE

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The gene transfer process begins when a functional copy of a mutated gene is created in a laboratory. The functional gene is developed to contain the instructions for making a needed protein.

BUILDING A TRANSPORT VEHICLE

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DNA is placed in the viral vector

The functional gene now has to be delivered into the body. To protect the gene and allow it to be introduced into the body, a transport vehicle is created from a neutralized virus.

The transport vehicle created from a neutralized virus is called a therapeutic vector. The neutralized virus is created by removing the inner viral material in a lab, leaving behind an empty protein shell.

Viruses used in gene transfer include adenovirusadeno-associated viruses (AAV), and lentiviruses. Ongoing studies are evaluating the body’s immune response to gene therapy.

DELIVERING THE FUNCTIONAL GENE

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A functional gene is placed inside the transport vehicle and large numbers are administered via an intravenous infusion. Once the transport vehicle has a functional gene inside, it is called a therapeutic vector. The therapeutic vector is designed to target the functional gene toward a preferred tissue. In hemophilia A and B, the liver is the target because it can make the proteins required for blood to clot. In other diseases, such as Huntington disease, the brain is the target.

When the functional gene is placed inside the AAV, additional DNA is included that is intended to allow it to work and promote production of the protein only within the targeted cells. Research is ongoing to understand to what extent the AAV may deliver the functional gene to the body’s other tissues.

MAKING PROTEINS

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Proteins in the body

Once introduced in the body, the new gene is designed to work in place of the gene that isn’t functioning properly. If successful, the goal for this new gene is to provide instructions for the body to make the protein it needs. In the case of hemophilia, the liver is targeted to make the proteins.

The new, functional gene enters the nucleus of the targeted cells. There, it is generally expected to reside as an episome, or circular piece of DNA, outside the chromosomes. The original genetic material found in the chromosomes is intended to be left unchanged. This means the mutated gene would still be there and can be passed on to a person’s offspring. In some cases, the gene integrates directly into the existing DNA. Research is ongoing to better understand the rate and impact of this integration.

Ongoing clinical trials are being conducted to understand how gene therapy will affect the human body. Please be sure to read through the section "WHAT ARE THE RISKS OF GENE THERAPY?"

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05
What are the goals
of gene therapy research?

Trials are evaluating the safety and whether the burdens of disease could be reduced

We typically take medicine to help us feel better, whether physically or mentally. In the case of gene therapy, clinical trials are underway to determine the risk and if, for some people, gene therapy could reduce or eliminate the need for ongoing treatment and the burdens of chronic disease. It’s important to remember that the long-term effects of gene therapy, including duration of effect, are also being studied and have not yet been determined.

SO, WHAT DO WE HOPE FOR FROM GENE THERAPY RESEARCH?

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Genes are the instructions for the body

Gene therapy aims to address specific mutations in an individual's genetic instructions, allowing the body to produce the proteins it needs.

INTRODUCING FUNCTIONAL GENES

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One goal of gene therapy being investigated is to introduce functioning genes into the body to try to target the mutations responsible for genetic conditions.

PRODUCING PROTEIN

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Also being researched is a way for the new, functional gene to help the body produce the protein needed to function properly. For example, in hemophilia A or B, the goal is to allow the body to produce factor VIII or factor IX, respectively, on its own.

POTENTIALLY REDUCING THE NEED FOR TREATMENT

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Research is ongoing to determine if gene therapy can help the body produce the proteins it needs. This may lead to less reliance on currently available medication.

POTENTIALLY ELIMINATING OR REDUCING SYMPTOMS

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Clinical trials are evaluating whether gene therapy could eliminate or reduce routine disease management. This in turn could possibly lessen the physical, mental, and emotional burden of a disease. Although gene therapy may not be able to address preexisting damage, it may be able to mitigate progression of any existing damage.

All of these goals as well as the risks are currently being evaluated in clinical trials in humans.

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06
What are the risks
of gene therapy?

Ongoing clinical trials are being conducted to determine the potential risks of gene therapy

Many forms of gene therapy are being researched only in adults, at least initially, and some gene therapies won’t work in patients with certain antibodies or other preexisting conditions. Gene therapy also comes with risks. Ongoing clinical trials are being conducted in people across many categories to determine the potential risks of treatment with gene therapy.

SAFETY IS A TOP PRIORITY

It’s important to understand that many safety precautions are being taken during the development of gene therapy. Clinical trials in the United States are closely monitored by the Food and Drug Administration and the National Institutes of Health. Based on an assessment by the FDA, there are more than 800 active gene therapy investigational new drugs currently on file with the FDA. Patient safety is the top priority. Ongoing clinical trials and research have identified some risks associated with gene therapy, and further research and experience may uncover additional risks that are currently unknown.

POTENTIAL RISKS

Gene transfer that uses an adeno-associated virus (AAV) vector to deliver the new genetic material may have several risks:

  • As with any virus, the body’s immune system could respond to the newly introduced therapeutic vector as if it were an intruder. An immune system reaction can lead to inflammation and other serious risks
  • An immune reaction could also make gene therapy work less effectively, or not at all. That is why prospective gene therapy patients are often screened to determine whether they have antibodies against a specific virus
  • While the objective of using a particular vector is to direct the new gene to a specific tissue type, viruses can affect other cells that weren’t targeted, potentially causing damage or additional illness or disease
  • After delivery of the gene therapy, vector particles can be released from the recipient's body. Called vector shedding, this can occur through feces, urine, saliva, and other excreted bodily fluids. Shedding raises the possibility of passing those remaining materials on to untreated individuals (through close contact). Its significance is currently being evaluated in gene therapy clinical trials
  • Whether gene therapy may have an adverse impact on the health of the organ or tissues targeted is being evaluated with long-term studies
  • Gene therapy may result in creation of too much of the protein. The effect of this overproduction, or overexpression, could vary based on the type of protein being created
  • For some patients, gene therapy may not work at all. And, it is not yet clear how long the effects of gene therapy may last

WE HOPE YOU NOW BETTER UNDERSTAND THE SCIENCE OF GENE THERAPY

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