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Gene therapy

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Contents

1.  Introduction

2.  Types of gene therapy

3.  Gene therapy work 

4.  Applications of gene therapy

5.  Vectors of gene therapy

6.  FDA process for gene therapy

7.  Advantages And Disadvantages

8.  Conclusion

9.  references

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INTRODUCTION

Gene therapy is the use of DNA as a pharmaceutical agent to treat disease. It derives

its name from the idea that DNA can be used to supplement or alter genes within an

individual's cells as a therapy to treat disease. The most common form of gene therapy

involves using DNA that encodes a functional, therapeutic gene to replace

a mutated gene. Other forms involve directly correcting a mutation, or using DNA

that encodes a therapeutic protein drug (rather than a natural human gene) to provide

treatment. In gene therapy, DNA that encodes a therapeutic protein is packaged within

a "vector", which is used to get the DNA inside cells within the body. Once inside, the

DNA becomes expressed by the cell machinery, resulting in the production of 

therapeutic protein, which in turn treats the patient's disease.

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TYPES OF GENETHERAPY

It having two types

1. Somatic gene therapy

2. Germ line gene therapy

Somatic gene therapy. 

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 trans gene (either 

integrated in the genome or as an external episome or plasmid) is used to treat a

disease in an individual.

Germline gene therapy.

In germ line gene therapy, germcells (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

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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 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  and higher risk than somatic gene therapy (e.g. using non-

integrative vectors). The USA has no federal legislation specifically addressing

human germ.

The wild type vs. (diminished germ line) data set was combined with the  fem-1(lf) 

(oocytes only) vs.  fem-3(gf) (sperm only) data set to generate the displayed set of 

genes with germline-enriched expression patterns. Reprinted with permission from

Reinke et al.

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Physical and chemical methods

Various physical and chemical methods were also tried to deliver therapeutic genes.

Microinjection of DNA and electro poration is not so suitable for invivo gene delivery

and is an expensive methodology.

Chemical methods include:

1.  5 either  invivo or  exvivo which bind to their complementary mRNA

sequences and hinder the protein synthesis. Antisense technology has been

successfully used in down-regulating k-ras and c-myc oncogenes expression.

Another recent gene therapy used to treat cancer is the “Suicide Gene   Therapy”. A

gene expressing toxic substance is targeted to the cancerous cells, causing the death of 

every cell expressing this suicidal gene.

Somatic gene therapy:

This involves inserting the correct gene into the somatic cells or somatic tissues to be

incorporated into the genome and function normally. However, this has its own

drawbacks:

line or somatic genetic modification (beyond the usual FDA testing

regulations for therapies in general).

Gene therapy can be done at two levels:

Germ line level ( Germ line gene therapy) and somatic cell level (somatic cell genetherapy).

is no certainty that the normal gene has evaded all cells of the system.

This would require repeated such therapies which are expensive and painful in

some cases.

Germ line gene therapy:

Germ line gene therapy involves correcting the defect caused by a mutated gene at the

germ line level.

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Being a foreign gene, though normal, may have deleterious side effects

The issue of human rights also come into play since when the individual learns

that his genetic material has been modified it would be too late to consider his say

Gene therapy though sounds like a boon to man kind, may actually prove to be a bane. It is possible to make designer babies with favorable characters

Gene therapy though only a decade old, has developed to an extent where somatic

gene therapy is ethically accepted and legalized. Every successful treatment

methodology used now was once a failure, having to even lose a few precious lives

and gene therapy is no exception. These failures however, were followed by more

innovative, flawless methods. Today, gene therapy is relatively widely employed in

the western countries and notably the success rates are higher than the failure rates if 

not 100%. Gene therapy has showed especially promising results with monogenic

disorders such as SCID, haemophilia etc. Soon, gene therapy would undoubtedly

gain a greater impact than antibiotics and immunization treatments prevalent today.

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Gene therapy work 

Gene therapy is designed to introduce genetic material into cells to compensate for 

abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary

 protein to be faulty or missing, gene therapy may be able to introduce a normal copy

of the gene to restore the function of the protein.

A gene that is inserted directly into a cell usually does not function. Instead, a carrier 

called a vector is genetically engineered to deliver the gene. Certain viruses are often

used as vectors because they can deliver the new gene by infecting the cell. The

viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene)

into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce

their DNA into the nucleus of the cell, but the DNA is not integrated into a

chromosome.

The vector can be injected or given intravenously (by IV) directly into a specific

tissue in the body, where it is taken up by individual cells. Alternately, a sample of the

 patient’s cells can be removed and exposed to the vector in a laboratory setting. Thecells containing the vector are then returned to the patient. If the treatment is

successful, the new gene delivered by the vector will make a functioning protein.

Researchers must overcome many technical challenges before gene therapy will be a

 practical approach to treating disease. For example, scientists must find betterways to

deliver genes and target them to particular cells. They must also ensure that new

genes are precisely controlled by the body.

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Applications of gene therapy

Conditions or disorders that result from mutations in a single gene are potentially the

 best candidates for gene therapy. However, the many challenges met by researchers

working on gene therapy mean that its application is still limited while the procedure

is being perfected.

Before gene therapy can be used to treat a certain genetic condition or disorder,

certain requirements need to be met:

  The faulty gene must be identified and some information about how it results

in the condition or disorder must be known so that the vector can be

genetically altered for use and the appropriate cell or tissue can be targeted.

  The gene must also be cloned so that it can be inserted into the vector.

  Once the gene is transferred into the new cell, its expression (whether it is

turned on or off) needs to be controlled.

 There must be sufficient value in treating the condition or disorder with genetherapy - that is, is there a simpler way to treat it?

  The balance of the risks and benefits of gene therapy for the condition or 

disorder must compare favourable to other available therapies.

  Once the above are met, researchers may be given permission to start clinical

trials of the procedure, which is closely monitored by institutional review

 boards and governmental agencies for safety.

Short-lived nature of gene therapy - Before gene psychiatric help can become a

 permanent cure for any condition, the therapeutic DNA introduced into target cells

must remain functional and the cell containing the therapeutic DNA must be long-

lived and stable. Problems with integrating therapeutic DNA into the genome and the

fast dividing nature of many cells prevent gene psychoanalysis from achieving any

long-term benefits. Patients will have to undergo multiple rounds of gene dream

therapy.

sometimes the new gene fails to express itself or the virus does not produce the

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Desiredresponse.

Immune response - Anytime a foreign object is introduced into human tissues, the

immune system have evolved to attack the invader. The risk of stimulating the

immune system in a way that reduces gene psychiatric therapy effectiveness is always

a possibility. Furthermore, the immune system's enhanced response to invaders it has

see before makes it difficult forgene therapy to be repeated surrounded by patients.

Problems with viral vectors - Viruses, while the carrier of choice in most gene

 psychiatric therapy studies, present a variety of potential problems to the patient --

toxicity, immune and inflammatory responses, and gene control and targeting issues.

In addendum, there is always ultigene disorders - Conditions or disorders that arisefrom mutations surrounded by 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 cause by the

combined effects of variations in many genes. Multigene or multifactorial disorders

suchas these would be especially difficult to treat effectively using gene psychiatric

help.

Chance of inducing a tumor (insertional mutagenesis) - The main problem thatgeneticists are encountering is the viruses may target the wrong cell.If the DNA is

integrated in the wrong place in the genome, for example in a tumor suppressor gene,

ethical and officially recognized problems - Many believe that this is an invasion of 

 privacy. They believe that if prenatal tests are performed that these could lead to an.

an individual's genes as tampering or corrupting God's work. the fear that the viral

Religious concerns - Religious groups and creationists may consider the alteration of 

vector, once inside the lenient, may recover its ability to cause disease.

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VECTORES OF GENETHERAPY

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 nano particles 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 plausiblestrategy 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. 

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 transfecton 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, lectropreoration, the gene gun, sono portion manage fiction and the use of 

oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticle.

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FDA REVIEW PROCESS FOR GENE THERAPY

For any unapproved biological product that is to be tested in humans, an IND must be

filed with FDA. The IND process for gene therapy is the same as it is for other 

 biologic products. We encourage and recommend meetings between CBER reviewers

and sponsors of a potential INDs for all biological products throughout the product

development process in order to stimulate scientific interchange and clarify FDA

regulatory requirements. Under statutory authority, FDA determines within 30

calendar days from receipt of an IND whether it is appropriate for the IND to proceed

or, if necessary, to place an IND on clinical hold, in order to protect the safety of 

human subjects. This is a difficult task for novel therapies with relatively unknown

risks.

Part of the FDA's review of the IND includes a review of the sponsor's proposed or 

FDA's recommended stopping rules. The stopping rules are rules in the protocol

which assure that a clinical trial will be stopped if certain adverse events should

occur. In addition, prior to allowing a clinical protocol to proceed under an IND, FDA

frequently requires several modifications to the protocol to ensure that all known

safety issues have been addressed. These might include: changes in manufacturing to

ensure purity, additional laboratory testing of the product, additional animal testing of 

a product, exclusion of human subjects who might be at high risk for serious adverse

events, additional safety testing of human subjects, lower starting doses in humans

and slower escalation of doses. These modifications to the protocol are intended to

lower the risk to human subjects.

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Advantages 

  arrests some diseases

  gives patients new genes, so they dont have the disease and the disease doesn't 

come back 

   provides as a way of treatment when in the past the disease would have been

incurable

  there have been several medical breakthroughs

  some people conisder it a great advancement for mankind

  Very effective when delivered to tissue correctly.

  You can avoid drug side effects.

  It fixes the problem at its source.

  gene therapy can eliminate and prevent hereditary diseases.

Disadvantages 

  In the past, gene therapy has cured some diseases, but caused others

  Its inconsistent

  Its a fairly new method, so there are still some glitches to it that scientists are

still figuring out.

  some people are against the ethics of it: some say its "playing God"

  the patient may have to undergo several therapy treatments

  hard to deliver genes efficiently throughout a tissue or system.

  It can be quite expensive.

  The long term effects of gene therapy are unknown.

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CONCLUSION

In the area of gene therapy, it is clear that many exciting innovations are emerging.

While many of these new gene therapy and biotech products may yet have unknown

risks, they also have the potential for tremendous patient benefit. When developing

these new products, sponsors of clinical trials must accept the responsibility to ensure

that participants are not exposed to known unreasonable risks and that the

experimental products are as safe as possible. I have outlined FDA's role in this

 process and have briefly mentioned our interactions with NIH. It is critically

important that sponsors and investigators who conduct the clinical trials take the

responsibility to assure the safety of their human subject participants. They must

achieve this by using quality controlled experimental products, by practicing good

clinical medicine and also by communicating accurate information to FDA regarding

safety in a timely manner, as required by our regulations.

CBER is committed to minimizing the risks to human subjects who participate in

clinical trials, including gene therapy studies, while encouraging the development of 

 promising new experimental therapies. We will continue to work closely with NIH

and others as appropriate. It is essential that FDA continue to develop the strongest

 possible science base so that our reviewers possess the necessary scientific and

medical knowledge to effectively review and evaluate new and increasingly complex

investigational biological products such as gene therapy.

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