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Taking gene therapy from the laboratory to the clinic involves many steps. Before trying
a therapy on human patients, researchers must:
- Understand the biology behind the disorder
- Develop the treatment approach
- Test its effectiveness in biological models of the disease
- Establish its safety in humans
Each of these steps requires the efforts of expert researchers and physicians, as well as funding
to support the research, approval by regulatory agencies, and time to obtain and analyze results.
Applying gene therapy can take a long time.
How long? Days, months, years?
Let's look at a real-life example: development of a gene therapy treatment
for a disorder called Adenosine Deaminase (ADA) deficiency. In the box below, you can examine the steps
needed to bring a therapy to the clinic. Milestones in developing the ADA gene therapy are boxed in blue.
Click on the "plus" icons to expand a topic, or click "expand all" to see the
entire procedure.
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STEP 1: Learn about the disease
Is the disorder a good candidate for gene therapy? To find out, study the disease.
1) Get money for the project
- Government research granting agencies
- Private investors
- Pharmaceutical companies
2) Get approval for the project
- From your organization's Institutional Review Board
3) Perform clinical research
- Diagnose and classify the disorder
- What are the signs and symptoms?
- Who gets the disorder? (Males or females? Specific ethnic groups?)
- At what age does the disorder appear?
- Clinical research on ADA deficiency began in the 1960s.
- Examine current treatments for the disorder
- What treatments are available?
- How effective are they?
- What are their drawbacks?
- What types of new treatments are needed?
- 1976: Blood transfusions show limited effectiveness and potential
immune system complications (graft-versus-host disease)
- 1987: First report of successful PEG-ADA treatment
- Publish your results in a peer-reviewed journal
4) Perform biological research
- Genetics
- Which gene(s) are involved in the disorder?
- What are the specific disease-causing mutations in these genes?
- 1974: Scientists map the ADA gene to a region on human Chromosome 20.
- 1986: The sequence of the ADA gene was first published.
- Cell biology
- What is the normal job of the protein encoded by the gene?
- How do mutations in the gene affect the protein's function?
- How does the altered protein influence cell and tissue function?
- 1960s-1980s: Scientists study the ADA protein, which works as an
enzyme. For ADA deficiency, the protein was identified
before the gene!
- Animal models
- What can you learn from animal models of the disorder?
- Publish your results in a peer-reviewed journal
5) DECISION: Is the disorder a good candidate for gene therapy?
STEP 2: Design a gene therapy
1) Use your knowledge of the disorder to design a gene therapy
- Which tissue do you need to target?
- How will you deliver the gene to the tissue? Which approach is more
appropriate, ex vivo or in vivo?
- 1985 - ADA deficiency affects cells of the immune system, which are present
in the blood and produced in the bone marrow. Therefore, an ex vivo approach was
deemed the safest and easiest method for gene therapy. This approach involves extracting
cells from the patient's bone marrow, treating them, and then putting them back
into the patient.
- How will you ensure that the gene gets into cells and starts working?
- What can go wrong?
- How will you know if sonething has gone wrong?
- What will you do if something goes wrong?
2) Test the therapy in appropriate models of the disease
- Test it in cells grown in the laboratory
- Test it in appropriate animal models
- Publish your results in a peer-reviewed journal
- 1985 - Researchers show that a retrovirus-based approach can deliver the ADA gene into cells taken from ADA patients.
- 1988 - Researchers show that the gene can be transferred safely and efficiently into the white blood cells of animals.
3) DECISION: Does your therapy look promising?
- If you think your therapy will work safely in human patients, proceed to Step 3
STEP 3: Get money and approval for clinical trials
1) Get money for the trials
- Government research granting agencies
- Private investors
- Pharmaceutical companies
2) Get approval for the trials
- From your organization's Institutional Review Board
STEP 4: Phase One clinical trial
1) Establish safety and dosage limits in a small group of people (20-80)
- Participants are usually terminally ill individuals who have not responded to other treatment.
- Is the treatment safe?
- At which doses is the treatment safe?
- What are the adverse side effects, if any?
- How will you address these side effects?
- Will the benefits of the treatment outweigh the risks?
- Publish your results in a peer-reviewed journal
- 1989 - Researchers establish the safety of an ex vivo ADA gene therapy in human cancer patients.
2) DECISION: Does your therapy still look promising?
- If you have established the safety and determined the dosage limits of the treatment, proceed to Step 5.
STEP 5: Phase Two clinical trial
1) Test the efficacy and safety in a larger group of people (100-300)
- Can you deliver the gene effectively to target cells?
- Do target cells express the delivered gene?
- Do you observe health improvements in study participants?
- Short-term?
- Long-term?
- Continue to measure side effects
- Publish your results in a peer-reviewed journal
- 1990 - The first clinical trial of ADA gene therapy in the United States began, using
two children diagnosed with ADA deficiency. The children's immune status improved after
they received the gene therapy; however, the therapy worked for only a few months and had
to be repeated several times over the next two to three years. In the years following the
treatment, periodic tests confirmed that the childrens reengineered cells are surviving and producing
the ADA enzyme. Over the long term, however, the procedures have shown mixed success. In
2003, the researchers reported that some of the first patient's cells still expressed the
delivered gene. The second patient developed an immune response to the
retrovirus gene delivery system, and few of her cells still express the transferred ADA gene.
- 1993 - In a different study, researchers performed gene therapy using the umbilical
cord blood stem cells from two infants born with ADA deficiency. Both patients continue to
express the transferred ADA gene in their immune cells. (For more about umbilical cord
blood stem cells, see the Stem Cells in the Spotlight module.)
2) DECISION: Is your therapy effective in a larger group of people?
STEP 6: Phase Three clinical trial
1) Test the therapy in a large group of people (1,000-3,000)
- Give treatment in a "double-blind" scenario. Neither the treating physicians nor
the patient knows whether the treatment is authentic or a "placebo" (control). This
ensures the validity of results.
- Publish your results in a peer-reviewed journal
2) DECISION: Is your treatment successful?
- If so, proceed to Step 7
- 2003 - No phase three human clinical trials for ADA deficiency have yet been conducted.
STEP 7: Get FDA approval for general clinical use
1) Write proposals, fill out paperwork, answer questions and wait for approval
- If approved, use your therapy to treat patients and proceed to Step 8
STEP 8: Phase Four clinical trial
1) Further test the efficacy and optimal use of the treatment in general use
- Publish your results in a peer-reviewed journal
Why does gene therapy approval take so long?
It's been more than 30 years since physicians began studying ADA deficiency and
more than 15 years since efforts to develop a gene therapy began in earnest. To date,
no ADA gene therapy has been successful enough to become common medical practice.
Why has this process taken so long? Gene therapy techniques were just emerging when researchers
began designing gene therapies for ADA deficiency. Although researchers employed the latest
technologies at the time, the first therapies were far from perfect.
Several major obstacles must be overcome before successful gene
therapies can be developed. These obstacles are discussed in Challenges in Gene Therapy.
As we learn more about how the human body works at the molecular level, gene therapies
will become more and more effective.
Supported by a Science Education Partnership
Award (SEPA) [No. 1 R25 RR16291-01] from the National Center for Research Resources, a component of the
National Institutes of Health, Department of Health and Human Services. The contents provided
here are solely the responsibility of the authors and do not necessarily represent the official
views of NCRR or NIH.
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About Adenosine Deaminase Deficiency
The first disease approved for gene therapy treatment was adenosine deaminase
(pronounced "a-DEN-oh-zeen dee-AM-in-ase") (ADA) deficiency, a rare genetic disorder. The ADA gene
encodes an enzyme called adenosine deaminase, which is needed for immune system function.
People with ADA deficiency lack normal ADA genes and cannot produce the functional ADA enzyme.
Children with this disorder have severe immunodeficiency and are prone to serious, sometimes
life-threatening, infections. Although ADA deficiency can be treated with a drug called PEG-ADA,
the drug costs more than $100,000 per year and it must be taken by injection for life.
ADA deficiency was selected for the first approved human gene therapy trial for several reasons:
- The disease is caused by a defect in a single gene, which increases the likelihood that
gene therapy will succeed.
- The gene is regulated in a simple, "always on" fashion, unlike many genes whose
regulation is more complex.
- The amount of ADA used in therapy does not need to be precisely regulated. Even small amounts of the enzyme
are known to be beneficial, and larger amounts are well tolerated by patients.
For more information about ADA and the first gene therapy clinical trial, see
Additional Resources.
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