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Hereditary Disease Foundation
Transplantation Planning Meeting
February 16, 1997
Coronado, California
Prepared by Patrick Brundin
Transplantation Planning Meeting
February 16, 1997
Coronado, California
Participants
Anne-Catherine Bachoud-Levi
EHESS
Anders Bjorklund
University of Lund
Patrik Brundin
University of Lund
Stephen Dunnett
University of Cambridge
Stephen Fink
Diacrin, Inc.
Fred Gage
The Salk Institute
Ole Isacson
Harvard Medical SchoolKarl Kieburtz
University of Rochester
Oleg Kopyov
Good Samaritan Hospital
Jeffrey Kordower
Rush Presbyterian Medical Center
Marc Peshanski
INSERM
Ethan Signer
Massachusetts Institute of Technology
Allan Tobin
University of California Los Angeles
Nancy Wexler
Columbia University
Transplantation Planning Meeting
February 16, 1997
Coronado, California
A new initiative
The Hereditary Disease Foundation (HDF) announced its program "Cure HD
Initiative" and the recruitment of Dr. Ethan Signer who will work full time for
HDF starting March 29th. He will direct the "Toward the Cure" initiative. An
anonymous 2 million dollar donation has laid an economic foundation for this
new initiative. In relation to neural transplantation in Huntington's disease
(HD), the overriding questions that need to be address include: What basic
research needs to be done to advance clinical application of neural
transplants in HD and how can HDF advance this research? How should
clinical transplantation trials in HD be designed?
Current status of neural grafting in HD
What is currently (February 1997) known about neural grafting in patients
with HD?:
In addition to a small number of HD patients grafted with neural tissue in
Mexico, (ex-) Czechoslovakia and Cuba, the number of operated HD
patients is 12 in the Good Samaritan (Los Angeles) program; 11 (xenografts)
in the Diacrin program and one in the Paris program. None of these studies
can, as yet, provide any conclusive information about the potential or
limitations of neural grafting in HD. It was pointed out that prompt publication
of information about grafted HD patients in scientific journals is important.
Published papers would add credibility to the field and one could avoid
having to discuss grafting studies only using information obtained from the
media. It was recalled that the adrenal medullary grafts performed in the late
eighties in patients with Parkinson's disease were actually damaging to the
neural transplantation field. It was felt that the absence of scientific rigor in
those trials and the initial paucity of reports of transplanted patients in the
scientific literature must not be repeated when it comes to neural
transplantation trials in HD. Marc Peschanski expressed fears that there had
not been sufficient pre-operative assessment of the HD patients operated so
far in Los Angeles. Moreover, he felt that more attention needed to be paid
to the risk of apparent improvement due to"retest"-effect during the
post-operative period. He also showed concern that a relatively large
number of patients were already operated, even though they were not
reported in the scientific literature. Oleg Kopyov defended the relatively
large number of patients and indicated that this was the minimum number
needed for statistically sound effects to be possible to detect, according to a
biostatistician.
Discussion on how HDF can contribute
An open discussion about the possible ways that HDF can promote research
on grafting in HD followed. It was made clear at the outset that HDF cannot
fund actual clinical trials, because this would be against the bylaws of HDF.
During the discussion the following areas/topics were identified as being
important to promote:
Discussion of optimal techniques for donor tissue preparation and safe.
intracerebral implantation of the tissue.
Standardization of clinical evaluation protocols.
Discussion of transplant imaging protocols.
Very serious consideration of the complex ethical issues at stake.
Promotion of publication/communication of results.
A continuous evaluation of whether neural transplantation the most
advantageous approach compared to other possible future neurosurgical
interventions in HD.
Promotion of links and communication between continents (specifically
the NECTAR-related groups in Europe and North American centers)
It was acknowledged that the Huntington Study Group (HSG) can provide an
important resource and infrastructure for several, but not all, of the
aforementioned points. While Anders Bj”rklund emphasized that a some
degree of consensus between neurologists, neurosurgeons and
neuroscientists would most certainly help the field, Karl Kieburtz pointed out
that at present there is no known neurosurgeon in the HSG.
Specific tasks for a future meeting hosted by the HDF
Subsequently the discussion focused more on identifying the type of
concrete issues that could be resolved in a future workshop arranged by
HDF.
For example, Jeffrey Kordower stated that any group participating in clinical
neural transplantation trials ought to have documented an ability to dissect
human (or pig) embryonic tissue. A future workshop could help define
criteria for a "correct" dissection. Karl Kieburtz pointed out that it would be
desirable if a working group could reach agreement whether there should be
a placebo control group or historical control groups or, alternatively, whether
two surgical arms should be considered. He also underscored the
differences in the ethical issues compared to those at hand when
transplanting in Parkinson's disease and poignantly expressed that (in HD)
"We are transplanting a family". Very special attention should be paid to how
information about the surgery is conveyed to transplantation candidates and
family members, especially those at risk of developing HD.
Marc Peschanski underlined again that "retest" effects must be carefully
considered in several of the clinical evaluation tests, and Nancy Wexler
pointed out that the effects of "expectation" in the operated patients must
also be taken into consideration.
Gradually the meeting came to a consensus that a future workshop should
be geared at defining the "bare minimum" for a clinical grafting trial in HD.
During the discussion, the terms "desirable" / "not tolerable" and
"vital"/"interesting" were introduced. It was hoped that a future workshop
could help to define, eg, what types of surgical procedures, clinical tests,
brain scans, types of consent forms etc, should be listed under each of these
headings when designing a trial. Anders Bj”rklund pointed out that even just
defining areas of clear agreement and disagreement between different
centers could be very useful. Fred Gage stressed the importance of
restricting the goals of a future workshop, and thereby increasing the
chances of useful agreements being reached.
Finally, it was agreed that the future workshop should take the form of a
Dalhem type conference:
Five topics for discussion were identified:
1. Graft tissue
2. Neurosurgery
3. Evaluation (Motor performance; Neuropsychology; Neuropsychiatry)
4. Imaging
5. Study design (including control groups, ethical issues, contacts with
families and the media etc)
Ideally, for each topic 6-8 people should be invited to form working groups.
Thus, the meeting should comprise 40-48 persons in total.
It was suggested that an medical ethicist (eg an IRB delegate) and a
representative for journalists should be included in the group working with
topic no. 5. To make the meeting more efficient aims should be drafted and
distributed before the meeting and when appropriate a questionnaire should
be distributed. This would help to define what information is already
available in the different centers.
Time point and location for the workshop
The time point and location for the workshop was suggested to be one of the
following (in order of preference)
1. 13-14 September; Location: Chicago or New York
2. Sometime in December: Miami.
Postscript: As new data stemming from research on transgenic mice have
come to the fore since this meeting, the Hereditary Disease Foundation has
temporarily postponed this workshop to concentrate on exploring the
implications of nuclear inclusions for the development of Huntington's
disease therapy. |
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