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Preimplantation HLA Typing: A Newsmaker Interview With Anver Kuliev, MD, PhD
Laurie Barclay, MD
May 5, 2004 — Editor's
Note: Preimplantation genetic diagnosis (PGD) can now allow human
leukocyte antigen (HLA) matching to affected siblings for stem cell
transplantation, according to a report of the first clinical experience
of preimplantation HLA matching not involving identification of a
causative gene, published in the May 5 issue of The Journal of the American Medical Association.
During 2002 to 2003, nine couples with children affected by bone
marrow failure requiring HLA-matched stem cell transplantation took
part in an in vitro fertilization (IVF) program with preimplantation
HLA-matching and selected embryo transfer. After testing 199 embryos,
the investigators selected 45 HLA-matched embryos (23%), of which 28
were transferred in 12 clinical cycles, resulting in five singleton
pregnancies and birth of five HLA-matched healthy children. The
Reproductive Genetics Institute in Chicago, Illinois, performed and
funded this study.
In an accompanying editorial, Norman C. Fost, MD, MPH, from the
University of Wisconsin Medical School in Madison, discusses the
benefits of this new genetic, reproductive, and transplantation
technology. However, he stresses the need to ensure biologic safety and
acknowledges that potential medical or psychological risks to the
resulting offspring are still unknown.
To learn more about this potentially ethically controversial
practice, Medscape's Laurie Barclay interviewed senior author Anver
Kuliev, MD, PhD, director of the Reproductive Genetics Research and
Education Center and director of the World Health Organization
Collaborating Center for Prevention of Genetic Disorders at the
Reproductive Genetics Institute.
Medscape: What are the advantages of preimplantation HLA typing and
selected embryo transfer, and how safe, effective, and cost-effective
is it?
Dr. Kuliev: The couples may have an HLA-identical baby
naturally with a 25% chance, or go through prenatal diagnosis, with the
same chance expected in each pregancy, but they would have to terminate
a nonmatched pregnancy, which would hardly be acceptable on ethical
grounds.
Preimplantation HLA typing allows selecting embryos before pregnancy
and provides the possibility of analyzing a dozen or more embryos at a
time, so that at least two or more HLA- identical (to the sibling with
malignant or nonmalignant bone marrow failure) embryos may be replaced
to yield a matched pregnancy and birth of a potential donor.
More than 1,000 healthy children have been born after the PGD
procedure, suggesting its safety and accuracy. Its effectiveness may be
demonstrated by the fact that it is not different from the
effectiveness of IVF, with no difference in pregnancy and take-home
baby rates. Although the cost-effectiveness consideration does not
apply to saving lives of children with lethal disorders, for whom
HLA-matched stem cell transplantation is the only hope, it is
incomparably [better than] finding a partial match through the
registries and the cost of bone marrow transplantation from partially
matched or nonmatched donors.
Medscape: Should the decision to undergo this procedure be made
solely by the couple under the guidance of their physician, or is there
a need for governmental or other regulation?
Dr. Kuliev: The decision is made solely by the couple under
the guidance of their physician [who is] taking care of the affected
sibling. There are, however, governmental regulations in some
countries, as described in the editorial in the same issue [of JAMA], and also some potential influences from specialized scientific societies, which, however, are not obligatory.
Medscape: What are the ethical issues regarding selection of
HLA-matched embryos intended for potential donor progeny for stem cell
transplantation, and destruction or cryopreservation of other embryos?
Dr. Kuliev: The approach allows overcoming the ethical
dilemmas of therapeutic cloning involving somatic cell nuclear
transfer, as a baby obtained through IVF is from both parents, as
[occurs] naturally. As two or three embryos are preselected for
transfer from approximately a dozen embryos available in IVF anyway,
[except that] the embryos are chosen based on morphologic parameters in
a standard IVF, there is no ethical issue involved in choosing these
two or three embryos based on their HLA type.
Medscape: The couples in this study apparently expressed their
desire to have another child, independent of the hope that that child
could serve as a stem cell donor for the affected sibling. Is it
important to verify this desire and, if so, how was that done? Should
couples whose primary motivation is to assist the affected sibling be
granted or denied the procedure?
Dr. Kuliev: There is no doubt that the couples desired to
have another child anyway, and their decision to have this child
matched to the sibling may be respected as they would like to do their
best for their child who will not live without a transplant. The
procedure involves so many efforts, [including the] IVF procedure with
all its requirements, that we have never had any experience of a couple
going though it for the sole purpose of treating a sibling, so there
was no need for consideration of granting or denying the procedure.
Medscape: What are the anticipated psychological sequelae of a
child learning he or she was selected as a potential donor, and is any
research or follow-up planned to investigate psychological outcomes?
Dr. Kuliev: This will need to be followed up, but the first child, [described in] our first article in JAMA [2001;285:3130-3133], is currently only three years old.
Medscape: What are the implications of informed consent for stem
cell or organ donation being granted by the same parents who selected
HLA-matched embryos intended to be compatible with their other
offspring needing transplantation?
Dr. Kuliev: There is no way we could foresee the implications
of parents' consent at the present time. The same consideration is
applied to parents giving consent for cord blood collection and storage
after birth.
Medscape: Could greater availability and acceptance of this
procedure lead to its use in other situations, for example, selection
of a suitable stem cell or organ donor for a relative other than a
sibling?
Dr. Kuliev: It will probably not, because collecting
umbilical cord blood stem cells at birth presents no harm for the baby,
in contrast to organ donation, unless the techniques are developed for
reprogramming cord blood stem cells to differentiate to any cell types
or organs.
Medscape: Would banking of frozen embryos ultimately lead to
availability of a wide selection of HLA types that might be in demand
by unrelated individuals in need of a compatible donor?
Dr. Kuliev: These considerations are similar to those
involved in the establishment of bank of embryonic stem cells. That is
a separate issue requiring a special debate currently underway in the
literature.
Medscape: Would regulatory mechanisms be needed to determine the suitability of this procedure under these circumstances?
Dr. Kuliev: They might be needed, but experience shows that
parents [with a] need for technology are so motivated to save the life
of their child that they are prepared to travel to those countries
where there is no such regulation.
Medscape: How likely is it that preimplantation genetic diagnosis
may ultimately lead to "designer babies" selected for physical or
mental attributes, and what would the ethical implications be?
Dr. Kuliev: Our experience shows that parents never requested
the selection of physical or mental attributes, [so it is not
pertinent] to discuss the ethical implications.
Medscape: Is there anything you would like to add in closing?
Dr. Kuliev: The approach seems to be a natural extension of
assisted reproduction practices to the selection of embryos based on
the genetic parameters, contrary to selection of embryos simply
depending on their morphology. This allows not only avoiding the
transfer of genetically compromised embryos and those with a poor
developmental potential, but also identifying embryos HLA-identical to
the siblings with life-threatening disorders requiring HLA-matched stem
cell transplantation.
JAMA. 2004;291:2079-2085, 2125-2126
Reviewed by Gary D. Vogin, MD
Laurie Barclay, MD is a freelance reviewer and writer for Medscape.
Medscape Medical News 2004. © 2004 Medscape
Send press releases and comments to news@medscape.net.
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