Gene Therapy in Parkinson's Disease: A Newsmaker Interview With Matthew During, MD, MSc
Laurie Barclay, MD

Aug. 21, 2003 — Editor's Note: Earlier this week at New York–Presbyterian Hospital, the first of 12 patients approved
by the U.S. Food and Drug Administration (FDA) for participation in a phase I trial received gene therapy for severe
Parkinson's disease via adeno-associated viral (AAV) vector-mediated somatic cell gene transfer. Under stereotactic
guidance, neurosurgeons infused into the subthalamic nucleus (STN) 3.5 billion viral particles, each bearing a copy of
a human gene for glutamic acid decarboxylase, an enzyme needed for production of the neurotransmitter gamma
aminobutyric acid (GABA).

Opponents of this treatment point to earlier disasters in gene therapy history, suggest that efficacy has not been
demonstrated adequately in primates, and express concern that viruses could replicate within the brain or shut down
neural transmission by overexpression of inhibitory proteins. Furthermore, therapeutic alternatives such as deep brain
stimulation (DBS) have been shown to be effective.

Although the main goal of this phase I trial is safety rather than efficacy, the investigators and their patients are
hoping to see some benefit within three months after surgery. To learn more about the implications and expectations of
this controversial therapy, Medscape's Laurie Barclay interviewed co-investigator Matthew During, MD, DSc, a professor
of molecular medicine at the University of Auckland in New Zealand. Dr. During is founder and consultant of Neurologix,
Inc., a company that has an interest in commercialization of gene therapy for neurologic disorders.
Medscape: What does the gene therapy procedure entail?

Dr. During: The surgery entails a stereotactic neurosurgical procedure under local anesthetic. First, magnetic
resonance imaging ([MRI] using a new generation 3T machine) is used to image the target region, the subthalamic nucleus
(STN). However, because millimeter accuracy is required, during surgery the STN is mapped using microelectrodes by
recording from single neurons as the electrode is slowly moved towards the STN using a microdrive. Once the signature
firing pattern of the STN is obtained, confirming that the electrode is in the STN, the fine wire electrode is pulled
out, leaving just the microelectrode sheath through which a hair-thin (170 µm) hollow vitreous silica fiber is
inserted. Thirty-five µL containing 3.5 billion particles of the viral vector, an AAV containing the human GAD gene
(cDNA), is then infused at 0.5 µL/min together with 15 µL 25% mannitol. After the 100-minute infusion period, the
delivery catheter is withdrawn and the wound closed.
Medscape: Based on animal models and other relevant data, what is the rationale for this procedure?

Dr. During: The rationale is based on both animal experiments as well as proof-of-principle human studies. We know
largely from primate studies, but also from human electrophysiological studies, that the STN is overactive in
Parkinson's disease, with increased burst and tonic firing of the neurons. This is because the degeneration of midbrain
dopaminergic neurons leads to loss of the normal inhibitory drive onto the STN; hence, it is disinhibited or
overactive. If you lesion the STN or electrically silence it by using very high frequency electrical stimulation,
typically around 130 Hz in DBS, the symptoms of Parkinson's are dramatically reduced. A colleague, Dr. Anders Lozano
from the University of Toronto, has published that the effects of DBS can be mimicked by the local infusion of
muscimol, a GABA agonist. These data suggest that strategies to inhibit or dampen the firing of the STN should lead to
clinical improvement. Because drug infusion lasts only a few minutes and requires a pump and a continuous supply of the
drug, it is not a practical procedure.

DBS is effective; however, it is associated with an approximate rate of 30% for adverse events, including infection,
erosions, disconnects, battery failures, and pain. This is in addition to the expense: $20,000 for the hardware alone;
the need for a second procedure carried out under general anesthesia for implantation of the stimulator in the chest;
as well as prolonged and repeated programming time. We believe that if we could obtain similar results to DBS but with
a simple one-shot injection approach, with no hardware and under local anesthesia, then this could be a considerable
advance and make the 10% to 15% of Parkinson's disease patients who could benefit from surgery more likely to receive
an effective therapy.

There is also some theoretical advantage of delivering the GAD gene to the STN over DBS, as the GABA production and
release occurs not only in the STN, but in the major afferent pathway in the internal segment of the globus pallidus
(GPi), which is also disinhibited in Parkinson's disease. Hence, the gene transfer into the STN leads to inhibition of
both the STN and GPi, both of which are targets for DBS. The critical animal experiments in support of this hypothesis
were published by our team in Science in October of 2002.
Medscape: How is the first patient doing after surgery?

Dr. During: He is doing great. He was discharged Aug. 20 from New York–Presbyterian Hospital. He has had no fever and
no complications. His MRI done two days after surgery shows no inflammation or changes in the STN, just trace evidence
of the microelectrode track leading to the STN.
Medscape: What are the expectations for this phase I trial?

Dr. During: First and foremost, safety. In the best-case scenario we would like to see some clinical benefit. This
first patient has largely unilateral disease, and we were limited by the FDA for this phase I study to perform
unilateral surgery only. The hope is to see clinical benefit even with this lowest dose — the trial includes four
patients in each of three dose cohorts, in a traditional open-label, dose-escalation design. We are also monitoring
surrogate markers, including 2-deoxyglucose PET, which we believe will be a good barometer of efficient gene transfer.
Medscape: What are the potential advantages and disadvantages of gene therapy compared with DBS and other alternatives?


Dr. During: The major advantages are no hardware; the entire procedure is carried out under local anesthetic; and
ultimately we believe this approach will prove safer than alternatives, including DBS. Although we used very precise
microelectrode mapping of the STN, in the future we believe that unlike DBS, where placement is absolutely critical
down to the millimeter, for gene transfer we could obtain good results even if we were several millimeters from the
midtarget zone. Hence, this surgery could be carried out by general neurosurgeons using simple MRI-guided stereotactic
procedures. In addition, DBS requires a lot of fiddling and involvement by the referring neurologist, who needs to
program the stimulator, and this is not always simple or straightforward. The 30% adverse event rate associated with
DBS is also not trivial, and we believe this should be much less with the AAV gene transfer.

The disadvantages of gene therapy largely relate to the unknowns. Nathan Klein is the world's first patient, and
therefore we have no evidence of efficacy. It just simply may not work or benefit him and other patients in the future.
Secondly, we are using a virus, which can potentially spread or be transported retrogradely by axons projecting to the
STN. If that happens, gene expression could occur in regions outside the STN, and this might lead to symptoms similar
to those associated with the use of benzodiazepines, drugs that act to facilitate GABA-ergic transmission.
Specifically, we might see drowsiness, sedation, and confusion, or potentially other neurologic deficits.

Finally, again because this is such a new approach, there may be untoward effects that are entirely unpredictable. The
vector may integrate at low efficiency, and this could disrupt normal gene function, again leading to neurologic signs
and symptoms. We have not seen evidence of this in our animal studies, including nonhuman primate safety testing, but
the human brain is different and hence there is always the risk of seeing something that was not apparent in the animal
studies.
Medscape: Are there other risks associated with gene therapy in general? How do they relate to this specific
application?

Dr. During: Several of the most concerning risks associated with gene therapy are less likely with this specific
application. The biggest concerns relate to toxicity and immunogenicity of the virus, leading to a major inflammatory
response or an overwhelming immune reaction similar to that which occurred with the unfortunate Jesse Gelsinger case.
Here, we are using a nonpathogenic virus, which does not elicit significant immune responses, particularly when given
directly into the brain, so we do not expect any inflammatory or immunological responses.

The next major concern is whether the vector integrates, and thereby disrupts the expression of normal genes,
particularly those involving regulation of the cell cycle. An example of this is the alarming cases of leukemia that
occured in two of the children enrolled in the French X-linked SCID protocol, in which high titer retroviruses were
used for gene delivery into hemopoietic stem and progenitor cells. This event, we believe, is not a significant risk in
our current protocol because first we are not using retroviruses, but AAV. Although AAV can integrate, they do so at a
much, much lower frequency, and again, unlike retroviruses, they have never been associated with an oncogenic event.

Moreover, in the target cells in our protocol, postmitotic neurons, activation of oncogenes leads not to the formation
of cancer, but to apoptosis of the transduced cells. Hence, even in the worst-case scenario with activation of an
oncogene in the target brain region, the cells would die, not form a brain tumor. Ablation of the STN is an
experimental therapy of Parkinson's disease and is carried out in places where the costs of DBS are prohibitive, and it
shows some efficacy. So this event would likely cause clinical benefit, not harm to the patient.
Medscape: What do you envision as the future role of gene therapy in Parkinson's disease and in other neurodegenerative
disorders?

Dr. During: We believe that ultimately gene therapy will replace other surgical approaches, not only to Parkinson's
disease but also to epilepsy and potentially to other neurologic disorders. There was much excitement earlier this
month about the Science paper on AAV gene therapy of amyotrophic lateral sclerosis, for example. Those investigators
also commented that they plan to proceed to clinical trials. We envisage gene therapy being complementary to drug
therapy and part of mainstream medicine in the future.

Reviewed by Gary D. Vogin, MD

Laurie Barclay, MD Writer for Medscape Medical News

Medscape Medical News is edited by Deborah Flapan, assistant managing editor of news at Medscape. Send press releases
and comments to [log in to unmask]

SOURCE: Medscape Medical News
http://www.medscape.com/viewarticle/460396

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