Gene Therapy Advisory Committee: Report on the Potential Use of Gene Therapy In Utero



# Background

## 1.
Since gene therapy was first attempted in 1989, there have been over 300 clinical protocols approved world wide. 30 Research trials in patients have been considered in the UK by the Gene Therapy Advisory Committee (GTAC) established in 1993 to review such work.

## 2.
There is a wide consensus that, at present, gene therapy should be restricted to attempts to modify somatic (body) cells so that changes will not be passed to successive generations. GTAC has confirmed that its view remains that gene modification of the germ line, where effects could be transmitted to offspring, should not yet be attempted.

## 3.
To date, all but two of the trials of somatic gene therapy considered by GTAC have been intended to be performed in adults or young persons over 16 years. The two exceptions were in young children born with inherited single gene disorders, Hurler's Disease and Severe Combined Immuno-Deficieney (SCID), where it may be possible to correct the gene deficiency before serious or life threatening symptoms develop.

## 4.
However in many genetic disorders it may not be possible to use such potential therapies after birth. In some disorders the damage is already done before birth and there may be good clinical reasons to intervene in utero to try and correct the genetic damage.

## 5.
Interventions in utero are not new. Surgical procedures are used to correct the accumulation of fluid in the bladder or chest; steroid drugs can be infused into the developing fetus and transfusion of blood or platelets directly into the fetus are established procedures.

## Stem cell transplantation

## 6.
To the list above, we must now add stem cell transplantation. There is considerable scientific and clinical interest in pluripotent haematopoietic stem cells (PHSC) -those cells that can self renew and which produce all lineages of blood cell formation. The potential to use PHSC before birth to treat congenital disease in theory offers a number of possible advantages. (i) Because the fetal immune system has not yet developed, it will not reject foreign cells. Unlike bone marrow transplantation post-birth there is no need to match donor cells.
[formula] (ii) [/formula]
The fetus will become "tolerant" to the foreign cells allowing for further treatment after birth, again without the risk of rejection. (iii)
Intervention in utero will permit "correction" of a disorder before clinical manifestations have developed.

## 7.
There is already a considerable body of evidence, from animal models and from a small number of in utero transplantations of unmodified bone marrow progenitor cells in human fetuses, that there is a "window of opportunity" that technically permits and favours engraftment of transplanted PHSC in utero.

## 8.
There have already been a small number of such trials during human pregnancies involving such disorders as X-linked SCID, -thalassaemia, sickle cell anaemia and -thalassaemia. 9.
Possible sources of human PHSC include cord blood, fetal liver, adult bone marrow and adult peripheral blood. The use of cells derived from another fetus raises both practical and ethical issues, and to date much work has concentrated upon the use of adult derived cells as a renewable, low risk and ethically acceptable source of PHSC. 10.
The technical aspects of in utero cell transplantation may be less complex than one might at first imagine. The fetal circulation can be accessed transabdominally under ultrasound from 17 weeks gestation. This technique is well established, in standard practice and the risks associated with it are well documented. The experimental technique of coelocentesis which accesses the exolcoelomic cavity by transvaginal puncture, may offer the possibility of stem cell engraftment much earlier in gestation (10 + weeks). Such very early interventions do not raise the issue of fetal awareness and pain (The Royal College of Obstetricians and Gynaecologists Working Party Report on Fetal Awareness, October 1997, concluded that it is not possible for the fetus to be aware of events before 26 weeks' gestation).

## The potential use of gene therapy in utero

## 11.
A second approach will build on the PHSC trials described above and will apply genetically modified cells in utero -i.e.in utero gene therapy. It has been argued that two key issues need to be addressed before such an intervention is considered; (i) that there must be a clear advantage over post-natal gene therapy; (ii) that there must be an advantage over therapy with unmodified cells. 12.
Pre-natal gene therapy has been proposed as most appropriate in disorders which result in irreversible illness or death in the pre or neonatal period. Examples may include Type 2 Gaucher's Disease, Krabbe's disease, Hurler's Disease etc. Considerable interest in the possibilities of gene therapy in utero was also stimulated by a letter to the "Lancet" in March 1997 in which an adenovirus vector was used in utero to correct the cystic fibrosis phenotype in mice [bib_ref] Reversal of cystic fibrosis phenotype in mice by gene therapy in utero, Larsen [/bib_ref].

## Action by gtac

## 13.
At its September 1997 meeting GTAC agreed to establish a subgroup on New and Emerging Technologies (NETS). 14.
The remit of the subgroup is to aid GTAC to fulfil one of its terms of reference "to advise UK Health Ministers on developments in gene therapy research and their implications". The subgroup's function was to report to GTAC on areas of any new technology that may have implications for gene therapy research or techniques. 15.
The subgroup was asked to look at the potential of gene therapy in utero. Members were provided with the Minutes of the December 1994 meeting of the US Recombinant DNA Advisory Committee (RAC), which discussed this subject and a review based upon papers and posters presented at the "Second International meeting on in utero stem cell transplantation and gene therapy" held in September 1997 in Nottingham. 16.
NETS met to consider this subject in November 1997 and presented its report to GTAC in February 1998.

## Nets report on in utero gene therapy

## 17.
In considering the principles that should apply to in utero gene therapy, NETS first revisited and reaffirmed the six key elements currently employed by GTAC when considering gene therapy for adults and children. These were developed by GTAC upon the recommendations of the Clothier Committee Report of 1992. NETS concluded that these principles should also apply to in utero gene therapy. 18.
These six principles state that: recognising that some people, including young children, may not be able to give such consent, therapeutic research involving such patients must not put them at disproportionate risk. 19.
The subgroup kept these principles in mind as they discussed in utero therapy issues, considered the papers prepared by RAC and heard presentations from relevant experts. The subgroup considered some of the key issues raised by both stem cell transplantation (SCT) using PHSC and gene therapy interventions in utero. The group considered both the scientific validity and the potential treatment advantages of such therapies. 20.
The group considered that SCT in utero offered therapeutic opportunities for a wide range of genetic disorders, and that such techniques were much more likely to be used in the short term than in utero gene therapy. 21.
Fetal liver cells were identified as the transplant of choice with discrete scientific advantages over either cord blood or cells derived from adults. The subgroup noted that SCT with fetal liver cells is not a "new" technique having been first attempted in the UK over thirty years ago.

## 22.
The subgroup agreed that there are ethical issues involved in the use of fetal tissues -those identified in the Polkinghorne Report "Review of the Guidance on the Research Use of Fetuses and Fetal Material". The NETS subgroup endorsed the code of practice recommended by the Polkinghorne Committee. Particular consideration should be given to those who might decline the use of fetal tissue whilst consenting to SCT using other donor tissue. 23.
In considering in utero gene therapy the subgroup agreed that it was unlikely to be feasible in the short term. Reasons included the lack of a strong list of candidate disorders for potential therapy, and that at this stage, SCT offered better prospects for success. 24.
The subgroup concurred with RAC's concern that in utero gene therapy may give rise to germ line effects. It was noted that in a sheep model it had been possible to transmit a gene insert in utero into multiple organs and tissues and to have the foreign gene(s) pass to subsequent generations.

## 25.
The subgroup considered that there were particular concerns about the risk of germ line involvement in the use of a direct, or vector, mediated gene therapy in vivo. Such interventions are unacceptable in view of the safety and ethical difficulties that remain at present. 26.
In contrast, the subgroup considered that the use of genetically modified stem cells in SCT was a possibility. Such ex vivo modification would be unlikely to carry with it any higher risk to the germ line than the trials of post natal somatic gene therapy which have already been approved. They agreed that ex vivo genetic modification prior to in utero SCT does not raise any new ethical concerns and could be considered by GTAC in the same manner as somatic gene therapy.

# Conclusions

## 27.
Following their discussion, the subgroup concluded that: (a) they did not consider that there were any new ethical issues raised by in utero gene therapy that were not already recognised in other interventions in utero, or in the use of gene therapy in other situations. The issue of consent remains a matter solely for the pregnant woman.
[formula] (b) [/formula]
In order to be ethical, the risks of the physical procedures would need to be known. (c)
The disorder or disease treated would need to be life threatening, or associated with severe disability, and for which no suitable treatment is available after birth, in order to justify intervention in utero.
[formula] (d) [/formula]
Existing concerns with regard to gene therapy, in particular regarding the potential for germ line transmission, remain. Such concerns would need to be fully answered in the event of any protocols proposing in utero gene therapy being presented to GTAC. (e)
With this in mind, GTAC believes that the use of a direct, or vector, mediated gene therapy in utero is unlikely to be acceptable for the foreseeable future, in view of the safety and ethical difficulties. (f) Somatic gene therapy protocols which involve ex vivo genetic modification of stem cells prior to bone marrow transplantation in infants have already received approval from GTAC. The Committee believes that stem cell transplantation in utero would be unlikely to carry with it significantly higher risk to the germ line than such post natal somatic gene therapy. (g) Such interventions could be considered by GTAC in the same manner as somatic gene therapy, i.e. subject to the strict criteria already established by the Committee.