Gene Therapy Woes

[Guest guest]

29 Mar 2005 14:00:33 -0000

 

Gene Therapy Woes

press-release

 

 

 

 

The Institute of Science in Society Science Society

Sustainability http://www.i-sis.org.uk

 

General Enquiries sam Website/Mailing List

press-release ISIS Director m.w.ho

========================================================

 

 

ISIS Press Release 29/03/05

 

Gene Therapy Woes

****************

 

Research continues to turn up new obstacles and dangers, and

tough questions are raised over the ethics involved. Dr.

Mae-Wan Ho

 

The sources for this article is posted on ISIS members'

website http://www.i-sis.org.uk/full/GTWFull.php. Details

here http://www.i-sis.org.uk/membership.php

 

Toxic shock and leukemia

 

The public first became aware of the dangers of gene therapy

when healthy teenage Jesse Gelsinger died in September 1999

as the result of volunteering for a clinical trial for the

inherited condition Ornithine Transcarbamylase Deficiency.

He died of toxic shock after receiving the adenovirus vector

carrying the transgene. The ensuing enquiry turned up more

than 600 serious adverse events (including deaths) in other

gene therapy clinical trials that were unreported, because

they were deemed related to the trial procedure ( " Failures

of gene therapy " , SiS 16

http://www.i-sis.org.uk/isisnews/sis16.php).

Gelsinger's father sued the research team and subsequently

settled out of court for an undisclosed amount.

 

In October and December 2002, the Necker Hospital in Paris

announced that the two youngest boys enrolled into a gene

therapy study for the treatment of X-SCID had developed a

form of leukaemia ( " Gene therapy's first cancer victim " , SiS

17 http://www.i-sis.org.uk/isisnews/sis17.php). The

retroviral vector had inserted near the gene LMO2, which

encodes a transcription factor, whose over-expression has

been implicated in child-hood T-cell acute lymphoblastic

leukaemia.disorders. One child has died. A third infant has

developed leukaemia by January 2005, which prompted the US

Food and Drug Administration to suspend three gene-therapy

trials on SCID in the US. The US Panel has announced that

gene therapy for X-linked SCID could proceed only if

patients have failed to respond to other treatments. This

restriction does not apply to other SCID cases.

 

These two incidents highlight the two major obstacles to

gene therapy and the dangers posed: immune reactions against

the vectors and transgenes, and inappropriate insertion of

vectors and transgenes that can cause mutations leading to

cancer.

 

Viral vectors tend to integrate into genes

 

It is not easy to get foreign genes into the genome, and

certainly they cannot be targeted to specific sites. But the

insertion sites are not random; they are worse than that.

Viral vectors of all kinds tend to insert preferably into

genes, and especially those most actively expressed, thus

causing the disruption ( " Gene therapy risks exposed " , SiS 19

http://www.i-sis.org.uk/isisnews/sis19.php). They also tend

to insert into regions rich in mobile genetic elements that

move gene sequences around the genome, thereby compromising

the stability of the inserts. In addition, deletions of host

DNA tend to occur at the site of insertion.

 

Immune responses

 

Gene therapy vectors usually contain parts of bacteria,

viruses, or other microorganisms. Immune responses can occur

to the viral vector, the transgene product as well as the

bacterial plasmid DNA.

 

Viruses are naturally able to incorporate foreign genetic

material in the host cell genome, and therefore are good

vectors for gene therapy. However, fighting infection by

bacteria and viruses is among the key functions of the

immune system. So, bacteria (plasmids) and viruses or parts

of them promptly trigger an `innate' immune response as soon

as they enter the body, causing cytokine production and an

influx of nonspecific inflammatory cells (macrophages,

dendritic cells, NK (natural killer) cells, and others).

 

`Adaptive' immunity is stimulated later, when antigen-

presenting cells (APCs) carrying antigens from the

microorganisms migrate to the lymph nodes. It includes the

production of neutralizing antibodies circulating in the

blood that are specific of the vector or transgene antigen,

and a cell-mediated response involving T cells and NK cells.

Adaptive immunity not only contributes to eliminating the

vectors and infected cells from the body but also results in

a memory response that undermines further attempts to use

the same vector or transgene.

 

Viral vectors are the most likely to induce an immune

response, especially those derived from adenovirus and

adeno-associated virus (AAV), which express immunogenic

proteins within the organism. The innate inflammatory

response is high with adenoviral vectors, and almost nil

with AAV vectors. Plasmid DNA vectors, because of the

presence of CpG dinucleotides, also tend to stimulate the

innate inflammatory response.

 

Specific `adaptive' immune responses are due to capsid

antigens in adenoviruses and AAV. Viral gene-encoded

proteins in adenoviruses can also be immunogenic. In the

case of retroviral vectors, the immune response is mainly

directed at the transgenes located within the vector rather

than the antigens in the vectoritself. Nonetheless, when

used in vivo, they are inactivated in the serum by

complement activation and can also trigger a cytotoxic

response, in which cells containing the vector are killed.

 

Risks and questionable ethics

 

Bioethicist Jonathan Kimmelman at McGill University,

Montreal, Canada, writing in the British Medical Journal in

January 2005, highlighted the special risks involved in gene

therapy and call for a " central ethical review " of all trial

protocols as well as " high scientific standards " for

clinical trials.

 

First, active agents rather than chemicals are used in gene

therapy. The vectors are potentially capable of propagating

and recombining with other viruses. Second, genetic

information is transferred which directly participates in

gene expression. Third, it involves both vector and

transgene, each of which carries its own risks, but the two

may act synergistically to worsen the risks, as in the

leukemia that occurred in the X-linked SCID trial; which may

be due to the combined toxicity of the vector integrating

near an oncogene and the transgene that may have helped to

transform T cells. Fourth, gene transfer agents that stably

modify cells can involve risks with long latencies, and

increase the probability of subtle toxic effects over the

long term. This is particularly relevant to treating

children, who may be more sensitive to the long-term hazards

because their tissues are still developing. Age may indeed

have been a factor in the leukemia cases in the X-linked

SCID trial. Risks to third parties are possible, such as

descendents of the patient getting insertion mutagenesis

through the inadvertent modification of germ cells, or the

transmission of infectious agents arising in the patient to

the general population. Finally, much of the toxicity

related to gene therapy is mediated through the immune

system (see above).

 

There are also problems over safety testing. Animal models

are often inadequate, as viruses that are pathogenic in

humans often behave differently in animals. People

previously exposed to viruses similar to the vector can

influence their response to the gene transfer, and the dose-

toxicity response could be nonlinear.

 

Although none of the individual risks is unique, the

frequency with which they occur in gene therapy trials and

at the same time make the risk of gene therapy distinctive.

 

" The complexity of risk from gene transfer militates against

the practice of using only local ethics committees to review

trials " wrote Kimmelman.

 

Furthermore, all major ethic codes require that clinical

research be capable of generating valuable medical

knowledge. But gene transfer trials have often failed to do

so.

 

Kimmelman pointed out that no gene therapy has been

commercialized after 15 years. And because of the

uncertainties surrounding gene transfer, " most trials should

be conceptualized less as testing an agent's prospect of

commercialization and more as producing information that can

be applied to the development of gene transfer. "

 

The same uncertainties make it unethical to recruit healthy

volunteers in clinical trials. But if only participants with

advanced illness are recruited, such participants are likely

to misinterpret the purpose of the trial as providing

therapy rather than providing general knowledge; in which

case, enrolment in such studies is susceptible to being

based on " misinformed " consent. And it is also easy for the

experimenter to misinterpret adverse events and deaths as

unrelated to the treatment.

 

 

 

========================================================

This article can be found on the I-SIS website at

http://www.i-sis.org.uk/GTW.php

 

If you like this original article from the Institute of

Science in Society, and would like to continue receiving

articles of this calibre, please consider making a donation

or purchase on our website

 

http://www.i-sis.org.uk/donations.

 

ISIS is an independent, not-for-profit organisation

dedicated to providing critical public information on

cutting edge science, and to promoting social accountability

and ecological sustainability in science.

 

 

========================================================

CONTACT DETAILS

 

The Institute of Science in Society, PO Box 32097, London

NW1 OXR

 

telephone: [44 1994 231623] [44 20 8452 2729] [44 20

7272 5636]

 

General Enquiries sam Website/Mailing List

press-release ISIS Director m.w.ho

 

MATERIAL ON THIS SITE MAY BE REPRODUCED FOR ANY PROFIT FREE

PURPOSES WITHOUT PERMISSION, ON CONDITION THAT IT IS

ACCREDITED ACCORDINGLY AND CONTAINS A LINK TO http://www.i-

sis.org.uk/.

ANY COMMERCIAL USE MUST BE AGREED WITH ISIS