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Review Article

Human Gene Therapy : A Brief Overview of the

Genetic Revolution
Sanjukta Misra*

Abstract
Advances in biotechnology have brought gene therapy to the forefront of medical research. The prelude to
successful gene therapy i.e. the efficient transfer and expression of a variety of human gene into target cells has
already been accomplished in several systems. Safe methods have been devised to do this, using several viral
and no-viral vectors. Two main approaches emerged: in vivo modification and ex vivo modification. retrovirus,
adenovirus, adeno-associated virus are suitable for gene therapeutic approaches which are based on permanent
expression of the therapeutic gene. Non-viral vectors are far less efficient than viral vectors, but they have
advantages due to their low immunogenicity and their large capacity for therapeutic DNA. To improve the function
of non-viral vectors, the addition of viral functions such as receptor mediated uptake and nuclear translocation of
DNA may finally lead to the development of an artificial virus. Gene transfer protocols have been approved for
human use in inherited diseases, cancers and acquired disorders. In 1990, the first successful clinical trial of gene
therapy was initiated for adenosine deaminase deficiency. Since then, the number of clinical protocols initiated
worldwide has increased exponentially. Although preliminary results of these trials are somewhat disappointing,
but human gene therapy dreams of treating diseases by replacing or supplementing the product of defective or
introducing novel therapeutic genes. So definitely human gene therapy is an effective addition to the arsenal of
approaches to many human therapies in the 21 st century.

Introduction • An abnormal gene could be swapped for a normal gene

homologous recombination
J ames Watson was quoted as saying “we used to think that our
fate was in our stars, but now we know, in large measures,
our fate is in our genes”. Genes, the functional unit of heredity,
• An abnormal gene could be repaired through selective
reverse mutation
are speciic sequences bases that encode instructions to make • Regulation (degree to which a gene is turned on or of) of
proteins. Although genes get a lot of atentions, it is the proteins a particular gene could be altered
that perform most life functions. When genes are altered, Gene therapy states and remains an experimental discipline
encoded proteins are unable to carry out their normal functions, and many researches remain to be performed before the
resulting in genetic disorders. Gene therapy (use of genes as treatment will realize its potential. Majority of the gene therapy
medicines) is basically to correct defective genes responsible for trials are being conducted in united States and europe, with
genetic disorder by one of the following approaches-1,2 only a modest number in other countries including Australia.
• A normal gene could be inserted into a nonspeciic location Scope of this approach is broad with potential in treatment of
within the genome to replace the Nonfunctional gene (most diseases caused by single gene recessive disorders (like cystic
common) ibrosis, hemophilia, muscular dystrophy, sickle cell anemia
Infectious etc), acquired genetic diseases such as cancer and certain viral
diseases infections like AIDS,3,4 as shown in figure 1.
Monogenic Other gene therapy projects are targeted at conditions such
10% diseases as heart disease, diabetes mellitus, arthritis and Alzheimer’s
disease, all of which involve genetic susceptibility to illness.5
14%
Table 1 shows a summary of approved current clinical gene
therapy protocols
6%
Other
70%
diseases Historical Perspectives
Since the earliest days of plant and animal domestication,
about 10,000 years ago, humans have understood that
Cancer characteristics traits of parents could be transmited to their
ofspring. The irst to speculate about how this process worked
were ancient Greek scholars, and some of their theories remained
Fig. 1 : Proportion of protocol for human gene therapy trials relating
in favor for several centuries. The scientiic study of genetics
to various types of diseases52
began in 1850s, when Austrian monk Gregor Mendel, in a
*
Asst. Professor, Dept. of biochemistry, Institute of Medical Sciences series of experiments with green peas, described the patern
and SuM Hospital, bhubaneswar 751 003, Orissa of inheritance, observing that traits were inherited as separate
received: 09.06.2011; revised: 29.02.2012; Accepted: 29.02.2012 units we know as genes. Mendel’s work formed the foundation

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Table 1 : Summary of approved and published current clinical gene therapy protocols50
Disorder Objective Target cells Mode of delivery Countries with protocols
ADA deiciency ADA replacement blood retrovirus Italy, the Netherlands,
united States
Alpha-1-antitrypsin Alpha-1-antitrypsin respiratory epithelium Liposome united States
deiciency replacement
AIDS Antigen presentation HIV blood, marrow blood, retrovirus united States
inactivation marrow
Cancer Immune function blood, marrow, tumour retrovirus, liposome, Austria, China, france,
enhancement electroporation, cell- Germany, Italy, the
mediated transfer Nethelands, united States
Tumour ablation Tumour retrovirus, non-complexed united States
DNA, cell-mediated transfer
Chemoprotection blood, marrow retrovirus united States
Stem-cell marking blood, marrow, tumour retrovirus Canada, france, Sweden,
united States
Cystic ibrosis Cystic ibrosis respiratory epithelium Adenovirus, liposome united Kingdom, united
transmembrane regulatory States
enzyme replacement
familial replacement of low-density- Liver retrovirus united States
hypercholesterolemia lipoprotein receptors
fanconi’s anemia Complement group C gene blood, marrow retrovirus united States
delivery
Gaucher’s disease Glucocerebrosidase blood, marrow retrovirus united States
replacement
Hemophilia b factor IX replacement Skin ibroblasts retrovirus China
rheumatoid arthritis Cytokine delivery Synovium retrovirus united States
for later scientiic achievements that heralded the era of modern technical diiculties and ethical reasons make it unlikely
genetics. But litle was known about the physical nature of genes that germ line therapy would be tried in human beings in
until 1950s, when American biochemist James Watson and british near future.
biophysicist francis Crick developed their revolutionary model 2. Somatic gene therapy:8 where therapeutic genes are transferred
of double stranded DNA helix. Another key breakthrough into the somatic cells of a patient. Any modiications and
came in the early 1970s, when researchers discovered a efects will be restricted to the individual patient only and
series of enzymes that made it possible to snip apart genes at will not be inherited by the patients ofspring or any later
predetermined site along a molecule of DNA and glue them back generation.
together in a reproducible manner. Those genetic advances set
Gene delivery
the stage for the emergence of genetic engineering, which has
produced new drugs and antibodies and enabled scientists to In most gene therapy studies, a normal gene is inserted into
contemplate gene therapy. A few years after the isolation of genes the genome to replace an abnormal, disease causing gene. Of
from DNA, gene therapy was discovered in 1980s.6 all challenges, the one that is most diicult is the problem of
gene delivery i.e. how to get the new or replacement gene into
Process of Gene Therapy the patient’s target cells. So a carrier molecule called vector
must be used for the above purpose.9 The ideal gene delivery
Approach
vector should be very speciic, capable of eiciently delivering
The process of gene therapy remains complex and many one or more genes of the size needed for clinical application,
techniques need further developments. The challenge of unrecognized by the immune system and be puriied in large
developing successful gene therapy for any speciic condition is quantities at high concentration. Once the vector is inserted
considerable. The condition in question must be well understood, into the patient, it should not induce an allergic reaction or
the undying faulty gene must be identiied and a working copy inlammation. It should be safe not only for the patient but also
of the gene involved must be available. Speciic cells in the for the environment. finally a vector should be able to express the
body requiring treatment must be identiied and are accessible. gene for as long as is required, generally the life of the patient .
A means of eiciently delivering working copies of the gene to
Two techniques have been used to deliver vectors i.e. ex-vivo
the cells must be available. Moreover diseases and their strict
and in-vivo.10 The former is the commonest method, which uses
genetic link need to be understood thoroughly.
extracted cells from the patient. first, the normal genes are cloned
Types of gene therapy into the vector. Next, the cells with defective genes are removed
There are 2 types of gene therapy. from the patient and are mixed with genetically engineered
1. Germ line gene therapy:7 where germ cells (sperm or egg) are vector. finally the transfected cells are reinfused in the patient
modiied by the introduction of functional genes, which to produce protein needed to ight the disease. On the contrary,
are integrated into their genome. Therefore changes due to the later technique does not use cells from the patient’s body.
therapy would be heritable and would be passed on to later Vectors with the normal gene are injected into patient’s blood
generation. Theoretically, this approach should be highly stream to seek out and bind with target cell (figure 2).
efective in counteracting genetic disease and hereditary Some of the vectors used in gene therapy include:
disorders. but at present many jurisdictions, a variety of

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Also this has been tried to treat SCID due to ADA

deiciency with relative success. As researchers have
grown more confident, they have begun injecting
altered retroviruses directly into tissues where the
corrected genes are needed. for example- in cystic
ibrosis (mutated gene impairs lung function), healthy
genes are inserted directly to the lining of bronchial
tube. experimental animal studies are being conducted
to establish the efect in muscular dystrophy.
• Adenovirus16
To avoid problem of inserting genes at wrong sites,
some researchers have turned to other types of viruses.
A class of virus with double stranded DNA genome
that can cause respiratory, intestinal and eye infection
(especially the common cold).When these viruses infect
a host cell, they introduce their DNA molecule into
the host. The genetic material of the adenovirus is not
Fig. 2 : Gene therapy using an adenovirus vector51 incorporated into the host cell’s genetic material. The
DNA molecule is left free in the nucleus of the host
A. Viral Vector cell, and the instructions in this extra DNA molecule
One of the most promising vectors currently being used are transcribed just like any other gene (figure 1).
is harmless viruses. Viruses have evolved a way of Adenovirus also can infect a broader a broader variety
encapsulating and delivering their genes to human cells in of cells than retrovirus, including cells that divide more
a pathogenic manner. Scientists have tried to take advantage slowly, such as lungs cells. However, adenovirus also
of this capability and manipulate the viral genome and are more likely to be atacked by the patient’s immune
replace them with working human gene.11 This altered system, and the high levels of virus required for
virus can then be used to smuggle genes into cells with treatment often provoke an undesirable inlammatory
great eiciency. Some of the viruses insert their genes into response. Despite these drawbacks, this vector system
the host genome, but do not actually enter the cell. Others has been promoted for treating cancer of liver and
penetrate the cell membrane disguised as protein molecule ovaries and indeed the irst gene therapy product to be
and enter the cell. Once the transplanted gene is ‘switched licensed to treat head and neck cancer is Gendicine, p53
on’ in the right location within the cell of an infected person, based adenoviral product.17 Concern about the safety
it can then issue instructions necessary for the cell to make of the above vectors was raised after the 1999 death of
the protein, that was previously missed or altered . Jesse Gelsinger while participating in a gene therapy
Some of the diferent types of viruses used as gene therapy trial.18 Since then, work using adenovirus vector has
vectors: focused on genetically crippled version of the virus.
• Retrovirus12 • Adeno-associated viruses [AAVs]
first viruses to be used as vectors in gene therapy One of the most promising potential vectors is a recently
experiments were retroviruses. They belong to a discovered virus called the AAV, which infects a broad
class of viruses (rNA as genetic material ) which can range of cells including both dividing and non dividing
create double stranded DNA copies with the enzyme cells. AAVs are small viruses from the Parvovirus
reverse transcriptase. These copies of its genome can be family with a genome of single stranded DNA. It can
integrated into the chromosome of host cell by another insert genetic material at a speciic site on chromosome
enzyme carried the virus called integrase. Now the 19 with near 100% certainty. researchers believe that
host cell has been modiied to contain a new gene. If most people carry AAV which do not cause disease
such modiied host cells divide later, their descendants and do not provoke an immune response. Scientists
will contain the new genes. Although retroviruses have demonstrated the animal experiments using
have been used in most gene therapy experiments AAV to correct genetic defects.18 It is now being used
so far, they present problems.13 One such problem is in preliminary studies to treat hereditary blood disease
that integrase enzyme can insert genetic material of hemophilia, muscle and eye disease. Also clinical trials
the virus into any arbitrary position in the genome of have been initiated to use AAV vectors to deliver genes
the host, which can lead to insertional mutagenesis (if to brain as the virus can infect nondividing cells like
insertion is in the middle of the gene) or uncontrolled neurons in which their genome are expressed for a long
cell division (if gene happens to be one regulating cell time.
division) leading to cancer. This problem has recently The chief drawback of AAV is that it is small, carrying
begun to be addressed by utilizing zinc inger nuclease14 only 2 genes in its natural state. Its payload therefore
or by including certain sequences such as beta globin is relatively limited. It can produce unintended genetic
locus control region to direct the site of integration to damage because the virus inserts its genes directly into
speciic chromosome. host cell’s DNA. Researchers have also had diiculties
Gene therapy trial using retroviral vector to treat in manufacturing large quantities of the altered virus.
X-linked severe combined immune deiciency represent The production problem has recently being solved by
the most successful application till date.15 Amsterdam Molecular Therapeutics.19 The recombinant

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DNA, which does not contain any viral genome and that, because of its construction and autonomy, the body’s
only the therapeutic gene, does not integrate into immune system would not atack it.
the genome, instead fuses at its end to form circular, The advantage of direct transfers of non-complexes
episomal forms which are predicted to be the primary or protein- complexed DNA by chemical, mechanical,
cause of long term gene expression. electrical, particle bombardment method or artificial
• Herpes simplex virus [HSV] chromosome method include the possibility of transferring
It is a human neurotropic virus, which is mostly used for relatively large DNA fragments. However, these processes
gene transfer in nervous system. It has a large genome are still ineicient, are limited to ex-vivo gene transfer and
compared to other viruses, which enable scientist to have undeined cytotoxic efects.21
insert more than one therapeutic gene into a single Target tissues for gene therapy
virus, paving the way for treatment of disorders caused Hematopoietic cells derived from bone marrow (bM) may
by more than one gene defect. HSV makes an ideal be readily obtained and manipulated ex-vivo in a variety
vector as it can infect a wide range of tissues including of tissue culture system. 25 furthermore, therapies based
muscle, liver, pancreas, and nerve and lung cells. The on transfer of genetically modified hematopoietic cells are
wild type of HSV-1 virus is able to infect neurons which potentially applicable to a wide range disorders, including
are not rejected by immune system.20 Antibodies to the hemoglobinopathies, AIDS and cancer. for these reasons,
HSV-1 are common in humans, however complications bM cells are attractive targets in gene therapy research.25
due to herpes infections are somewhat rare. Gene transfer into human hematopoietic stem cells capable
B. Non-Viral Methods of proliferating in-vivo for long period of time, giving rise
Simplest method of non-viral transfection is direct DNA to large number of progeny expressing the desired product,
injection.21 Clinical trials to inject naked DNA plasmids remains an elusive goal. The main limitation is related to the
have been performed successfully. There have been trials fact that hematopoietic cells greatest potential for proliferation
with naked PCr products, which have had greater success. are generally quiescent and resistant to retrovirus mediated
Research eforts have yielded several non-viral methods gene transfer.26 Meanwhile, the utility of genetically modiied
gene transfer such as electroporation (creation of electric hematopoietic cells, with limited but predictable proliferative
ield induced pores in plasma membrane), sonoporation potential continues to be elevated.25
(ultrasonic frequencies to disrupt cell membrane), research into the usefulness of other cell types as gene
magnetofection (use of magnetic particle complexed with transfer vehicle remains very active. The known regenerative
DNA), gene guns (shoots DNA coated gold particles into properties of the liver make it an attractive gene transfer
cells by using high pressure) and receptor mediated gene target. Disorders theoretically amenable to this form of therapy
transfer are being explored.22 each method has its own include familial hypercholesterolemia, hemophilia, urea cycle
advantages and disadvantages. defect, -1-antitrypsin deiciency and phenylketonuria.27 Other
Among the several nonviral approaches, receptor mediated potential targets for therapy include skeletal muscle cells for
gene transfer currently holds the most promise. This amelioration of muscular dystrophies, respiratory epithelial
application involves the use of DNA conjugated with cells for the treatment of respiratory insuiciency in cystic
speciic proteins (viral structural protein), or with liposome, ibrosis, and central nervous system tissue for degenerative
or both.22 under experimental ex-vivo conditions, liposomes neurologic disorders.20,28 The utility of carrier cells expressing
containing DNA have been shown to undergo cellular exogenous genes in nonantigenic porous microcapsules has also
uptake through endocytosis, with subsequent transient been demonstrated, and this method promises long term gene
exogenous gene expression. Nevertheless, the application delivery using “universal donor” cell lines.29 In a more radical
of this approach will likely be limited until methods for the experimental approach, implantable “neo-organs” made up
stable integration of the endocytosed DNA are devised and of genetically modiied carrier cells bound to collagen coated
improvement in target ability, transfection eiciency and synthetic ibres have been shown to have the capacity to become
DNA carrying capacity are developed.22,23 vascularized intraperitoneally and to secrete proteins.30

recently several chemical methods like use of synthetic

oligonucleotides (to inactivate defective genes by using
Journey of Clinical Trials in Gene
antisense speciic to target gene), lipoplexes (made up of Therapy [1980 – 2010]
anionic and neutral lipids) and polyplexes (complex of There are several early speculations on the method of gene
polymers with DNA) have been used to facilitate delivery of therapy.31 In 1966, Tatum predicted that viruses could be used
the DNA into cell.24 recently there have been some hybrid to convert genes in theoretical studies in somatic-cell genetics.
methods developed that combine two or more techniques. The irst atempt in genetics was done in Pecking ducklings
for example- vibrosomes that combine liposomes with an which were injected with DNA extracts from Khaki Campbell
inactivated HIV or inluenza virus. This has been shown to ducks and expressed some of the characteristics of the said duck
have more eicient gene transfer in respiratory epithelial but another trial on albino rat by DNA extracts of pigmented
cell than either viral or liposomal method alone. Other rat did not produce any signiicant result. In 1970, American
hybrid methods involve mixing viral vectors with cationic doctor Stanield Rogers tried to treat two sisters, sufering from
lipids. researchers are also experimenting with introducing arginemia (that lacks enzyme arginase, a type of protein) by
a 47th (artiicial human) chromosome into target cells. This injecting shope papilloma virus containing an arginase gene but
chromosome would exist autonomously alongside the this gene therapy was unsuccessful to raise the above protein
standard 46, not afecting their workings or causing any levels higher. In 1977, scientists were able to use gene therapy
mutation. It would be a large vector capable of carrying technique to deliver a gene into cells of mammals.
substantial amount of genetic code, and scientists anticipate

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In 1980, Mercola and Cline32 undertook the irst human gene because viral vectors are too big to get across the blood brain
therapy trial to treat β thalassemia patients by transfecting barrier. This method has potential for treatment for Parkinson’s
β globin gene into human bone marrow cells. This protocol disease.
lacked appropriate ethical review, was widely reviewed as Scientists at the National Institute of Health (bethesda,
premature on scientiic grounds and was eventually stopped. Maryland) have successfully treated metastatic melanoma in two
Two important points emerged from this study. One was the fact patients using killer T cells genetically retargeted to atack the
that highly regulated and coordinated expression of both ά-like cancer cells. This study constitutes one of the irst demonstrations
and β-like globin genes would likely be required for successful that gene therapy can be efective in treating cancer. In another
gene therapy of the hemoglobinopathies. Other was the need development, gene therapy may be used to Huntington’s disease.
to address the safety and ethical concern adequately in clinical Short interfering rNAs (sirNAs) are designed to match the rNA,
trials of gene therapy. copied from a faulty gene and to produce abnormal protein
In 1990, American doctor Anderson performed one of the product of that gene. This rNA interference or gene silencing
irst successful gene therapy study on a 4 year old girl named may be used in gene therapy to switch of Huntington’s disease.39
Ashanti DeSilva, with a rare genetic immune system disorder In 2005, scientists were able to repair deafness in guinea pig
called severe combined immuno-deiciency (SCID). The lack by using adenovirus vector.40 Atoh1 gene (which stimulates hair
of production of adenosine deaminase (ADA), had made her cell’s growth) was delivered to cochlea resulting in regrowth of
immune system weak, so she had become susceptible to many hair cells and so regaining 80% of original hearing threshold.
severe diseases. Anderson and his colleagues extracted her This study may pave the way to human trials of gene therapy
WbCs, implanted genes producing ADA into WbCs and then in such cases.
transferred the cells back to her body. The WbCs strengthened
In 2006 (March), an international group of scientists
the girl’s immune system made it possible for her to survive.
announced the successful use of gene therapy to treat two adult
The efects were only temporary, but successful.33
patients for a disease afecting myeloid cells.41 Study published
In 1992, Claudio bordignon of Italy performed the first in Nature Medicine, is believed to be the irst to show that gene
procedure of gene therapy using hematopoietic stem cells as therapy can cure disease of myeloid system. In May 2006, a
vectors to deliver genes intended to correct hereditary disease.34 team of scientists from Italy, reported a breakthrough for gene
In 1993, a new born baby Andrew Gobea, with SCID, was therapy in which they developed a way to prevent immune
treated by gene therapy technique using retrovirus vector system from rejecting a newly delivered gene with the use of
carrying ADA gene.35 blood was removed from his placenta and micro rNAs, whose natural function could be used to selectively
umbilical cord immediately after birth, containing stem cells. turn of the identity of the therapeutic gene.42 The researchers
retrovirus (carrying ADA gene) and stem cells were mixed, were successful in mice experimentation. This work will have
after which they entered and inserted the gene into stem cells’ important implication for the treatment of hemophilia and other
chromosome. Stem cells containing the working ADA enzyme genetic disease by gene therapy. In August 2006, researchers
were also given weekly. for next few years, WbCs (produced successfully reengineered immune cells, called lymphocyte,
by stem cells), made ADA enzyme using ADA gene. After then to target and atack cancer cells in patients with advanced
further treatment was needed. metastatic melanoma. This is the irst time that gene therapy
In 1999, gene therapy sufered a major setback with the death is used to successfully treat cancer in humans. In November
of 18 year old Jesse Gelsinger who participated in a gene therapy 2006, Preston Nix from the university of Pennsylvania School of
trial for ornithine transcarboxylase deiciency.18 He died from Medicine reported on VrX496, a gene-based immunotherapy for
multiple organ failure 4 days after starting the treatment. His the treatment of human immunodeiciency virus(HIV) that used
death was believed to have been triggered by a severe immune a lentiviral vector for delivery of an antisense gene against the
response to the adenovirus carrier. HIV envelope. Patients responded to the above therapy showing
stable and increased immune response (CD4 T cell count). This
In 2002, french researcher Alain fischer tried to cure children
was the irst evaluation of a lentiviral vector administered in
sufering from X- linked SCID (also known as bubble boy)
u.S. food and Drug Administration-approved human clinical
by inserting retrovirus carrying normal gene into children’s
trials for any disease.43 Data from an ongoing clinical trial were
blood stem cell. This clinical trial was questioned when 2 of
presented at CrOI (conference on retrovirus and opportunistic
them developed a leukemia-like condition.36 However another
infection)
major blow came in Jan 2003, when the “fOOD and DruG
ADMINISTrATION” [fDA] placed a temporary halt on all In 2007, a team of British doctors from Mooreield’s Eye
gene therapy trials using retrovirus vector in blood stem cells. Hospital and university college of London, announced the
Then in April 2003, fDA eased the ban after regulatory review world’s irst gene therapy trial to test a revolutionary gene
of the protocol in uSA, uK, france, Italy and Germany37 since therapy treatment for a type of inherited retinal disease i.e.
the treatment had beneited a large number of children. Leber’s congenital amaurosis, which is caused by mutation
in the rPe65 gene. Sub-retinal delivery of recombinant AAV
researchers at Case Western reserve university and
carrying rPe65 yielded positive result, with patient having
Copernicus Therapeutics have been able to create DNA nanoballs
modest increase in vision, and more importantly, no apparent
(tiny liposomes 25nm) that can carry therapeutic DNA through
side-efect.44
pores in nuclear membrane. Moreover gene therapy approach
repairs errors in messengerrNA derived from defective genes. In 2009 (March), the School of Pharmacy in London tried
This technique has the potential to treat thalassemia, cystic nanotechnology based gene therapy (which delivers genes
ibrosis, and some forms of cancers. wrapped in nanoparticles) to target and destroy hard-to-reach
cancer cells.45 In September 2009, journal Nature reported that
In 2003, Los Angeles research team inserted genes into brain
researchers at the university of Washington and university of
using liposome coated in a polymer called polyethylene glycol.38
florida were able to give trichomatic vision to squirrel monkeys
The transfer of gene into brain is a signiicant achievement

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using gene therapy.46 This could have a signiicance on future with a corrective transgene using a retrovirus, and this led
treatment for colour blindness in humans. In November 2009, to the development of T cell leukemia in 3 of 20 patients.
the journal Science reported that researchers succeeded at halting
a fatal brain disease, adrenoleukodystrophy, using a vector Ethical and Social Consideration
derived from HIV to deliver the gene for the missing enzyme.47 Gene therapy is a powerful new technology that might have
In 2010, a paper by Komaromy et al. published in April 2010, unforeseen risks, scientists irst develop a proposed experiments
deals with gene therapy for a form of achromatopsia (complete i.e. protocol, that incorporates strict guidelines. After the approval
colour blindness) in dogs. It is presented as idle model to develop from fDA, the organization continues to monitor the experiment.
gene therapy directed to cone photoreceptor. Cone function In the course of a clinical trial, researchers are required to report
and day vision have been restored for at least 33 months in two any harmful side efects. Critics and proponents all agree that
young dogs with achromatopsia. However, the therapy was less risks of gene therapy must not be substantially larger than the
eicient for older dogs.48 potential beneit. Gene therapy poses ethical considerations for
people to consider.49 Some people are concerned about whether
Disadvantages of Gene Therapy gene therapy is right and it may be used ethically.
No therapy, established or experimental, is without some Some of the ethical considerations for gene therapy include:
associated risks. As human gene therapy is still a relatively new • Deciding what is normal and what is a disability;
procedure, there are still many risks associated with it. Scientists
• Deciding whether disabilities are diseases and whether they
do not yet understand all of the risks and there has not been
should be cured;
enough time to complete detailed studies on how gene therapy
works and the problems that it poses. Safety will appropriately • Deciding whether searching for a cure demeans the live of
remain an important consideration as the ield of gene therapy people who have disabilities;
evolves.13 Some of the problems of gene therapy include: • Deciding whether somatic gene therapy is more or less
• Short-lived nature of gene therapy: before gene therapy can ethical than germ line gene therapy
become a permanent cure for any condition, the therapeutic Initial experiments using gene therapy have been conducted
DNA introduced into target cells must remain functional primarily in patients for whom all other treatments have failed,
and cells containing the therapeutic DNA must be long-lived so that the risks are small. Many people feel that because gene
and stable. Problems with integrating therapeutic DNA therapies use altered genes and potentially dangerous viruses,
into the genome and the rapidly dividing nature of many those treatments should be tested more extensively.
cells prevent gene therapy from achieving any long-term
beneits. Patients will have to undergo multiple rounds of Conclusion
gene therapy. Moreover, the new gene fails to express itself
Most scientists believe the potential for gene therapy is the
or the virus does not produce the desired response.
most exciting application of DNA science, yet undertaken.
• Immune response: Anytime a foreign object is introduced into How widely this therapy will be applied, depends on the
human tissues, the immune system has evolved to atack simpliication of procedure. As gene therapy is uprising in the
the invader. The risk of stimulating the immune system in ield of medicine, scientists believe that after 20 years, this will
a way that reduces gene therapy efectiveness is always a be the last cure of every genetic disease. Genes may ultimately
possibility. furthermore, the immune system’s enhanced be used as medicine and given as simple intravenous injection
response to invaders makes it diicult for gene therapy to of gene transfer vehicle that will seek our target cells for stable,
be repeated in patient.12 site-speciic chromosomal integration and subsequent gene
• Problem with viral vectors: Viruses, while the carrier of expression. And now that a draft of the human genome map
choice in most gene therapy studies, present a variety of is complete, research is focusing on the function of each gene
potential problems to the patients- toxicity, immune and and the role of the faulty gene play in disease. Gene therapy
inlammatory response and gene control and targeting will ultimately play Copernican part and will change our lives
issues. In addition, there is always the fear that viral vector, forever.
once inside the patient, may recover its ability to cause
disease. References
• Multigenic disorders: Conditions or disorders that arise 1. Miller DA. Human gene therapy comes of age. Nature 1992;375:455-
460
from mutation in a single gene are best candidates for
gene therapy. unfortunately, some of the most commonly 2. Verma IM, Weizman MD. Gene therapy: Twenty-irst century
occurring disorders, such as heart disease, high blood medicine. Annu Rev Biochem 2005;74:711-738
pressure, Alzheimer’s disease, arthritis and diabetes, are 3. Knoell DM, yiu IM. Human gene therapy for hereditary diseases:
caused by the combined efects of variations in many genes. a review of trials. Am J Health Syst Pharma 1998;55:899-904
Multigenic or multifactorial disorders would be especially 4. Ginter eK.Gene therapy of hereditary disease. Vopr Med Khim
diicult to treat efectively using gene therapy.11 2000;46:265-78

• Insertional mutagenesis: The main problem that geneticists 5. Vandendriessche T. recent developments in gene therapy. Verh K
Acad Geneeskd Belg 2004;66:305-15
are encountering is the virus may target the wrong cells. If
the DNA is integrated in the wrong place in the genome,14 6. friedmann T. A brief history of gene therapy. Nature Genetics
1992;2:93-98
for example in a tumor suppressor gene, it could induce a
tumor. This has occurred in clinical trials for X-linked SCID 7. Mathews QL, Curiel DT.Grne Therapy: Human Gemline Genetics
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