Gene therapy using an
adenovirus vector. A new gene is inserted into a cell using an adenovirus. If the treatment is successful, the new gene will make a functional
protein to treat a disease.
Gene therapy is the use of
nucleic acid polymers as a
drug to treat disease by therapeutic delivery into a patient's cells, where they are either
expressed as proteins, interfere with the expression of proteins, or possibly even correct genetic mutations. The most common form of gene therapy involves using
DNA that encodes a functional, therapeutic
gene to replace a
mutated gene. In gene therapy, the nucleic acid molecule is packaged within a "
vector", which is used to get the molecule inside cells within the body.
Gene therapy was first conceptualized in 1972, with the authors urging caution before commencing gene therapy studies in humans. The first FDA-approved gene therapy experiment in the
United States occurred in 1990, when Ashanti DeSilva was treated for
ADA-
SCID.
[1] By January 2014, about 2,000 clinical trials had been conducted or had been approved using a number of techniques for gene therapy.
[2]
Although early clinical failures led many to dismiss gene therapy as over-hyped, clinical successes since 2006 have bolstered new optimism in the promise of gene therapy. These include successful treatment of patients with the retinal disease
Leber's congenital amaurosis,
[3][4][5][6] X-linked SCID,
[7] ADA-SCID,
[8][9] adrenoleukodystrophy,
[10] chronic lymphocytic leukemia (CLL),
[11] acute lymphocytic leukemia (ALL),
[12] multiple myeloma,
[13] haemophilia[9] and
Parkinson's disease.
[14] These clinical successes have led to a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field
[15][16] and between 2013 and April 2014, US companies invested over $600 million in gene therapy.
[17]
The first commercial gene therapy,
Gendicine, was approved in China in 2003 for the treatment of certain cancers.
[18] Glybera, a treatment for a rare inherited disorder, became the first gene therapy treatment to be approved for clinical use in either Europe or the United States in 2012 after its
endorsement by the European Commission.
[19][20]
Approach
Following early advances in
genetic engineering of bacteria, cells, and small animals, scientists have started considering how this technique could be applied to medicine; could human chromosomes be modified to treat disease. Two main approaches have been considered - adding a gene to replace a gene that wasn't working properly, or disrupting genes that were not working properly.
[21] Scientists focused on diseases caused by single-gene defects, such as
cystic fibrosis,
haemophilia,
muscular dystrophy,
thalassemia, and
sickle cell anemia. As of 2014, gene therapy was still generally an experimental technique, although in 2012
Glybera became the first gene therapy treatment to be approved for clinical use in either
Europe or the United States after its endorsement by the European Commission, as a treatment for a disease caused by a defect in a single gene,
lipoprotein lipase.
[19][20]
In gene therapy,
DNA must be administered to the patient, get to the cells that need repair, enter the cell, and express a protein in a medically useful way.
[22] Generally the DNA is incorporated into an engineered
virus that serves as a
vector, to get the DNA through the bloodstream, into cells, and incorporated into a
chromosome.
[23][24] However, so-called
naked DNA approaches have also been explored, especially in the context of
vaccine development.
[25]
Generally, efforts have focused on administering a gene that causes a protein to be expressed, that the patient directly needs. However, with development of our understanding of the function of
nucleases such as
zinc finger nucleases in humans, efforts have begun to incorporate genes encoding nucleases into chromosomes; the expressed nucleases then "edit" the chromosome, disrupting genes causing disease. As of 2014 these approaches have been limited to taking cells from patients, delivering the nuclease gene to the cells, and then administering the transformed cells to patients.
[26]
There are other technologies in which nucleic acids are being developed as drugs, such as
antisense,
small interfering RNA, and others. To the extent that these technologies do not seek to alter the chromosome, but instead are intended to directly interact with other biomolecules such as
RNA, they are generally not considered "gene therapy" per se.
[citation needed]
Types of gene therapy
Gene therapy may be classified into the two following types, only one of which has been used in humans:
Somatic gene therapy
As the name suggests, in somatic gene therapy, the therapeutic genes are transferred into the
somatic cells (non sex-cells), or body, of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations.
Somatic gene therapy represents the mainstream line of current basic and clinical research, where the therapeutic DNA transgene (either integrated in the genome or as an external episome or plasmid) is used to treat a disease in an individual.
Several somatic cell gene transfer experiments are currently in clinical trials with varied success. Over 600 clinical trials utilizing somatic cell therapy are underway in the United States. Most of these trials focus on treating severe genetic disorders, including
immunodeficiencies,
haemophilia,
thalassaemia, and
cystic fibrosis. These disorders are good candidates for somatic cell therapy because they are caused by single gene defects. While somatic cell therapy is promising for treatment, a complete correction of a genetic disorder or the replacement of multiple genes in somatic cells is not yet possible. Only a few of the many clinical trials are in the advanced stages.
[27]
Germline gene therapy
In germline gene therapy,
germ cells (sperm or eggs) are modified by the introduction of functional genes, which are integrated into their genomes. Germ cells will combine to form a zygote which will divide to produce all the other cells in an organism and therefore if a germ cell is genetically modified then all the cells in the organism will contain the modified gene. This would allow the therapy to be heritable and passed on to later generations. Although this should, in theory, be highly effective in counteracting genetic disorders and hereditary diseases, some jurisdictions, including Australia, Canada, Germany, Israel, Switzerland, and the Netherlands
[28] prohibit this for application in human beings, at least for the present, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations
[28] and higher risk than somatic gene therapy (e.g. using non-integrative vectors).
[29] The USA has no federal legislation specifically addressing human germ-line or somatic genetic modification (beyond the FDA testing regulations for therapies in general).
[28][30][31][32]
Vectors in gene therapy
Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by
a number of methods. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).
Viruses
All
viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Therefore this has been recognized as a plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA.
A number of viruses have been used for human gene therapy, including
retrovirus,
adenovirus,
lentivirus,
herpes simplex virus,
vaccinia,
pox virus, and
adeno-associated virus.
[2]
Non-viral methods
Non-viral methods can present certain advantages over viral methods, such as large scale production and low host immunogenicity. Previously, low levels of
transfection and
expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques that approach the transfection efficiencies of viruses.
There are
several methods for non-viral gene therapy, including the injection of naked DNA,
electroporation, the
gene gun,
sonoporation,
magnetofection, and the use of
oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.
Technological hurdles
Some of the unsolved problems with the technology underlying gene therapy include:
- Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
- Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients.
- Problems with viral vectors – Viruses, the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient: toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
- Multigene disorders – Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.
- For countries in which germ-line gene therapy is illegal, indications[33] that the Weismann barrier (between soma and germ-line) can be breached are relevant; spread to the testes, therefore could impact the germline against the intentions of the therapy.
- Chance of inducing a tumor (insertional mutagenesis) – If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.[34][35] One possible solution for this is to add a functional tumor suppressor gene onto the DNA to be integrated; however, this poses its own problems, since the longer the DNA is, the harder it is to integrate it efficiently into cell genomes. The development of CRISPR technology in 2012 allowed researchers to make much more precise changes at exact locations in the genome.[36]
- The cost - only a small number of patients can be treated with gene therapy because of the extremely high cost (Alipogene tiparvovec or Glybera, for example, at a cost of $1.6 million per patient was reported in 2013 to be the most expensive drug in the world).[37][38]
Deaths
Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of
Jesse Gelsinger in 1999,
[39] which represented a major setback in the field. One X-SCID patient died of leukemia following gene therapy treatment in 2003.
[1] In 2007, a rheumatoid arthritis patient died from an infection in a gene therapy trial; a subsequent investigation concluded that the death was not related to her gene therapy treatment.
[40]
Development of gene therapy technology
1970s and earlier
In 1972 Friedmann and Roblin authored a paper in
Science titled "Gene therapy for human genetic disease?"
[41] Rogers (1970) was cited for proposing that
exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.
[42]
1980s
In 1984 a retrovirus vector system was designed which could efficiently insert foreign genes into mammalian chromosomes.
[43]
1990s
The first approved gene therapy case in the United States took place on 14 September 1990, at the National Institute of Health, under the direction of Professor
William French Anderson.
[44] It was performed on a four year old girl named Ashanti DeSilva. It was a treatment for a genetic defect that left her with
ADA-
SCID, a severe immune system deficiency. The effects were only temporary, but successful.
[45]
In 1992 Doctor Claudio Bordignon working at the Vita-Salute San Raffaele University, Milan, Italy performed the first procedure of gene therapy using
hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.
[46] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase-deficiency (SCID). The success of a multi-center trial for treating children with SCID (
severe combined immune deficiency or "bubble boy" disease) held from 2000 and 2002 was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the United States, the United Kingdom, France, Italy, and Germany.
[47]
In 1993 Andrew Gobea was born with
severe combined immunodeficiency (SCID). Genetic screening before birth showed that he had SCID. Blood was removed from Andrew's placenta and umbilical cord immediately after birth, containing stem cells. The allele that codes for
adenosine deaminase (ADA) was obtained and was inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses entered and inserted the gene into the stem cells' chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood system via a vein. Injections of the ADA enzyme were also given weekly. For four years
T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.
[citation needed]
The 1999 death of
Jesse Gelsinger in a gene therapy clinical trial resulted in a significant setback to gene therapy research in the United States.
[48][49] As a result, the U.S. FDA suspended several clinical trials pending the re-evaluation of ethical and procedural practices in the field.
[50]
2000s
2002
Sickle-cell disease is successfully treated in mice.
[51] The mice – which have essentially the same defect that causes sickle cell disease in humans – through the use a viral vector, were made produce
fetal hemoglobin (HbF), which normally ceases to be produced by an individual shortly after birth. In humans, the use of
hydroxyurea to stimulate the production of HbF has long been shown to temporarily alleviate the symptoms of sickle cell disease. The researchers demonstrated this method of gene therapy to be a more permanent means to increase the production of the therapeutic HbF.
[52]
A new gene therapy approach repairs errors in messenger RNA derived from defective genes. This technique has the potential to treat the blood disorder
thalassaemia,
cystic fibrosis, and some cancers.
[53]
Researchers at
Case Western Reserve University and Copernicus Therapeutics are able to create tiny liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.
[54]
2003
In 2003 a
University of California, Los Angeles research team inserted genes into the brain using
liposomes coated in a
polymer called
polyethylene glycol. The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the
blood–brain barrier. This method has potential for treating
Parkinson's disease.
[55]
RNA interference or
gene silencing may be a new way to treat
Huntington's disease. Short pieces of double-stranded RNA (short, interfering RNAs or
siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.
[56]
Gendicine is a gene therapy to treat certain cancers; it delivers the
tumor suppressor gene
p53 using an engineered
adenovirus. In 2003, it was approved in China for the treatment of
head and neck squamous cell carcinoma.
[18]
2006
In March 2006 an international group of scientists announced the successful use of gene therapy to treat two adult patients for X-linked
chronic granulomatous disease, a disease which affects
myeloid cells and which gives a defective immune system. The study, published in Nature Medicine, is believed to be the first to show that gene therapy can cure diseases of the
myeloid system.
[57]
In May 2006 a team of scientists led by Dr. Luigi Naldini and Dr. Brian Brown from the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in
Milan,
Italy reported a breakthrough for gene therapy in which they developed a way to prevent the immune system from rejecting a newly delivered gene.
[58] Similar to
organ transplantation, gene therapy has been plagued by the problem of immune rejection. So far, delivery of the 'normal' gene has been difficult because the
immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as
microRNAs. Dr. Naldini's group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy.
In August 2006, scientists at the
National Institutes of Health (
Bethesda, Maryland) successfully treated metastatic
melanoma in two patients using
killer T cells genetically retargeted to attack the cancer cells. This study constitutes one of the first demonstrations that gene therapy can be effective in treating
cancer.
[59]
In November 2006 Preston Nix from the
University of Pennsylvania School of Medicine reported on VRX496, a gene-based
immunotherapy for the treatment of
human immunodeficiency virus (HIV) that uses a
lentiviral vector for delivery of an
antisense gene against the
HIV envelope. In the Phase I trial enrolling five subjects with chronic HIV infection who had failed to respond to at least two
antiretroviral regimens, a single intravenous infusion of
autologous CD4 T cells genetically modified with VRX496 was safe and well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. In addition, all five patients had stable or increased immune response to HIV
antigens and other
pathogens. This was the first evaluation of a lentiviral vector administered in U.S.
Food and Drug Administration-approved human clinical trials for any disease.
[60] Data from an ongoing Phase I/II clinical trial were presented at CROI 2009.
[61]
2007
On 1 May 2007
Moorfields Eye Hospital and
University College London's Institute of Ophthalmology announced the world's first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male,
Robert Johnson, in early 2007.
[62] Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the
RPE65 gene. The results of a small clinical trial in children were published in New England Journal of Medicine in April 2008.
[63] They researched the safety of the subretinal delivery of recombinant adeno-associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects.
2008
In May 2008, two more groups, one at the University of Florida and another at the University of Pennsylvania, reported positive results in independent clinical trials using gene therapy to treat Leber's congenital amaurosis.
In all three clinical trials, patients recovered functional vision without apparent side-effects.
[3][4][5][6] These studies, which used
adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.
2009
In September 2009, the journal
Nature reported that researchers at the
University of Washington and
University of Florida were able to give
trichromatic vision to
squirrel monkeys using gene therapy, a hopeful precursor to a treatment for
color blindness in humans.
[64] In November 2009, the journal
Science reported that researchers succeeded at halting a fatal
genetic disorder called
adrenoleukodystrophy in two children using a
lentivirus vector to deliver a functioning version of
ABCD1, the gene that is mutated in the disorder.
[65]
2010s
2010
A paper by Komáromy
et al. published in April 2010, deals with gene therapy for a form of
achromatopsia in dogs. Achromatopsia, or complete color blindness, is presented as an ideal model to develop gene therapy directed to cone photoreceptors. Cone function and day vision have been restored for at least 33 months in two young dogs with achromatopsia. However, the therapy was less efficient for older dogs.
[66]
In September 2010, it was announced that an 18 year old male patient in France with
beta-thalassemia major had been successfully treated with gene therapy.
[67] Beta-thalassemia major is an inherited blood disease in which
beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.
[68] A team directed by Dr. Phillipe Leboulch (of the
University of Paris, Bluebird Bio and
Harvard Medical School[69]) used a lentiviral vector to transduce the human ß-globin gene into purified blood and marrow cells obtained from the patient in June 2007.
[70] The patient's haemoglobin levels were stable at 9 to 10 g/dL, about a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions had not been needed.
[69][70] Further clinical trials were planned.
[71] Bone marrow transplants are the only cure for thalassemia but 75% of patients are unable to find a matching bone marrow donor.
[69]
2011
In 2007 and 2008, a man being treated by
Gero Hütter was cured of
HIV by repeated
Hematopoietic stem cell transplantation (see also
Allogeneic stem cell transplantation,
Allogeneic bone marrow transplantation,
Allotransplantation) with double-delta-32 mutation which disables the
CCR5 receptor; this cure was not completely accepted by the medical community until 2011.
[72] This cure required complete
ablation of existing
bone marrow which is very debilitating.
In August 2011, two of three subjects of a pilot study were confirmed to have been cured from
chronic lymphocytic leukemia (CLL). The study carried out by the researchers at the
University of Pennsylvania used genetically modified
T cells to attack cells that expressed the
CD19 protein to fight the disease.
[11] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.
[73]
Human HGF plasmid DNA therapy of
cardiomyocytes is being examined as a potential treatment for
coronary artery disease as well as treatment for the damage that occurs to the heart after
myocardial infarction.
[74][75]
2012
The FDA approved Phase 1 clinical trials of the use of gene therapy on
thalassemia major patients in the US. Researchers at Memorial Sloan Kettering Cancer Center in New York began to recruit 10 participants for the study in July 2012.
[76] The study was expected to end in 2015.
[77]
In July 2012, the
European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment, called
Alipogene tiparvovec (Glybera), compensates for
lipoprotein lipase deficiency, which can cause severe
pancreatitis.
[78] The recommendation was endorsed by the
European Commission in November 2012
[19][20] and commercial rollout is expected in late 2014.
[79][80]
In December 2012, it was reported that 10 of 13 patients with
multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered
T cells to target proteins NY-ESO-1 and LAGE-1 which exist only on cancerous myeloma cells. This procedure had been developed by a company called Adaptimmune.
[13]
2013
In March 2013, Researchers at the
Memorial Sloan-Kettering Cancer Center in New York, reported that three of five subjects who had
acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified
T cells which attacked cells with
CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients immune systems would make normal T-cells and B-cells after a couple of months however they were given bone marrow to make sure. One patient had relapsed and died and one had died of a blood clot unrelated to the disease.
[12]
Following encouraging Phase 1 trials, in April 2013, researchers in the UK and the US announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients
[81] at several hospitals in the US and Europe to use gene therapy to combat
heart disease. These trials were designed to increase the levels of
SERCA2a protein in the heart muscles and improve the function of these muscles.
[82] The
FDA granted this a
Breakthrough Therapy Designation which would speed up the trial and approval process in the USA.
[83]
In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months the results were promising. Three of the children had
metachromatic leukodystrophy which causes children to lose cognitive and motor skills.
[84] The other children had
Wiskott-Aldrich syndrome which leaves them to open to infection, autoimmune diseases and cancer due to a faulty immune system.
[85]
In October 2013, the
Great Ormond Street Hospital, London reported that two children born with
adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and their immune systems were showing signs of full recovery. Another three children treated since then were also making good progress. ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."
[9]
In October 2013, Amit Nathwani of the
Royal Free London NHS Foundation Trust in London reported that they had treated six people with haemophilia in early 2011 using genetically engineered adeno-associated virus. Over two years later all six were still producing blood plasma clotting factor.
[9][86]
2014
In January 2014, researchers at the
University of Oxford reported that six people suffering from
choroideremia had been treated with a genetically engineered adeno-associated virus with a copy of a gene
REP1. Over a six month to two year period all had improved their sight. Choroideremia is an inherited genetic eye disease for which in the past there has been no treatment and patients eventually go blind.
[87][88]
In March 2014 researchers at the
University of Pennsylvania reported that 12 patients with
HIV had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation known to protect against HIV (
CCR5 deficiency). Results were promising.
[89][90]
Speculative uses for gene therapy
Several uses for gene therapy have been speculated.
Gene doping
There is a risk that athletes might abuse gene therapy technologies to improve their athletic performance.
[91] This idea is known as
gene doping and is as yet not known to be in use but a number of gene therapies have potential applications to athletic enhancement. In some cases, scholars have argued that genetic technology can make doping safer and thus more ethically acceptable. For example, Kayser et al. argue that if anything, gene doping will level the playing field if all athletes receive equal access: this will ensure that all athletes compete solely on how well they are performing relative to their maximum potential. In other cases, scientists and medics consider that any application of a therapeutic intervention for non-therapeutic or enhancing purposes compromises the ethical foundation of medicine and the spirit of sport.
[92]
Human genetic engineering
It has been speculated that genetic engineering could be used to change physical appearance,
metabolism, and even
improve physical capabilities and mental faculties like
memory and
intelligence, although for now these uses are limited to
science fiction. These speculations have in turn led to ethical concerns and claims, including the belief that every fetus has an inherent right to remain genetically unmodified, the belief that parents hold the rights to modify their unborn offspring, and the belief that every child has the right to be born free from preventable diseases.
[93][94][95] On the other hand, others have made claims that many people try to improve themselves already through diet, exercise, education, cosmetics, and plastic surgery and that accomplishing these goals through genetics could be more efficient and worthwhile.
[96][97] This view sees the prevention of genetic diseases as a duty to humankind in preventing harm to future generations.
Genetic enhancement is considered morally contentious,
[98] however, and access to enhancement procedures will probably be regulated. Possible regulatory schemes include a complete ban of genetic enhancement, provision of genetic enhancement procedures to everyone, or a system of professional self-regulation.
Perhaps the most practical regulatory approach is the self-regulation of health professionals. The
American Medical Association’s Council on Ethical and Judicial Affairs has stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”
[99]
Evidence regarding clinical use of Gene Therapy
Data from three trials on Topical
cystic fibrosis transmembrane conductance regulator gene therapy were reported in 2013 not to support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections and outcomes studied in these trials were not of clinical relevance.
[100]
Clinical trials of gene therapy for
sickle cell disease were started in 2014
[101][102] although one review failed to find them.
[103]
Regulations
Policies on genetic modification tend to fall in the realm of general guidelines about human-involved biomedical research. Universal restrictions and documents have been made by international organizations to set a general standard on the issue of involving humans directly in research.
[citation needed]
One key regulation comes from the
Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects), last amended by the World Medical Association’s General Assembly in 2008.
[104] This document focuses on the principles physicians and researchers must consider when involving humans as the research subject. Additionally, the Statement on Gene Therapy Research initiated by the
Human Genome Organization in 2001 also provides a legal baseline for all countries. HUGO’s document reiterates the organization’s common principles researchers must follow when conducting human genetic research including the recognition of human freedom and adherence to human rights, and the statement also declares recommendations for somatic gene therapy including a call for researchers and governments to attend to public concerns about the pros, cons and ethical concerns about the research.
[105]
United States
No federal legislation specifically lays out protocol and restrictions about either germline or somatic human genetic engineering. Instead, this subject is governed by overlapping regulations from local and federal agencies. Included agencies, from the Department of Health and Human Services, are the Food and Drug Administration and the Recombinant DNA Advisory Committee of the National Institutes of Health. Additionally, researchers who wish to receive federal funds when conducting research about an investigational new drug application, which is commonly the case for somatic human genetic engineering, are required to obey international and federal guidelines dealing with the protection of human test subjects.
[106]
The
National Institutes of Health (NIH) mainly serves as the gene therapy regulator for federally funded research institutions and projects. Privately funded human genetic research can only be recommended to voluntarily follow their regulations. NIH provides funding for lab research that develops or enhances devices utilized in human genetic engineering and to evaluate the ethics and quality of science present in current research labs. The NIH maintains a mandatory registry of human genetic engineering research protocols from all federally funded projects. An advisory committee to the NIH published a set of guidelines on the manipulation of genes.
[107] The document for the NIH guidelines discusses safety considerations for the lab as well as for any human patient test subject. A wide range of various experimental types which involve any type of gene transfer or alteration are discussed. Several sections specifically pertain to human genetic engineering including Section III-C-1. This section states the review process researches must undergo and the aspects that are considered when attempting to be approved to begin clinical research involving human genetic transfer into a patient. This document is an important tool required for scientists to follow in order to further scientific progress in the field of somatic cell therapy.
[108]
The United States
Food and Drug Administration (FDA) regulates the quality and safety of gene therapy products and supervises how these products are implicated clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as
clinical trials, must be reviewed and approved by the FDA and an
Institutional Review Board.
[109][110]
Popular culture
