BY
CHARLES MOORE IN
NEWS.
Stem cell therapy, which many
people living with Parkinson’s disease have long pinned hope on as a potential
treatment or even a cure, is finally advancing to clinical trial stage. The
recent announcement of a Phase 1/2a clinical trial involving transplantation of
stem cells into the first human subjects is therefore raising hope among
patients that an effective stem cell-based treatment for Parkinson’s may
finally be just over the horizon. However, the announcement is also a
subject of discussion and debate in the research community.
Stem cells, described by The Michael J. Fox Foundation For Parkinson’s Research as a “renewable source of tissue that can be coaxed to become different cell types of the body,” help with maintenance and repair of body tissues by becoming specialized cell types of the tissue or organ where they originate, and are seen as having “potential to significantly impact the development of disease-modifying treatments for Parkinson’s disease.”
Parkinson’s disease (PD) is the second most common neurodegenerative disease — a chronic, degenerative neurological disorder, mainly affecting the motor system, caused by a shortage of the brain chemical dopamine that enables messages to be sent to the parts of the brain that control movement and some forms of thinking. Parkinson’s, which is currently incurable, affects approximately one in 100 people over the age of 60. Numbers of people living with the disease are estimated to be at least one million in the U.S. and five to seven million worldwide.
Currently, standard medications used to treat Parkinson’s, L-DOPA and dopamine agonists, improve early symptoms of the disease, but as it progresses and dopaminergic neurons continue to be lost, the drugs eventually become ineffective while at the same time frequently produce a complication that results in involuntary writhing movements.
Scientists are investigating how regenerative medicine and stem cell science could be used to treat or prevent Parkinson’s disease, and while the disorder’s underlying cause is still unknown, researchers do know which cells and areas of the brain are involved, and have been experimentally successful in using stem cells to grow dopamine-producing nerve cells in the lab.
However, the Fox Foundation
cautions that while stem cell research has the potential to significantly
impact development of disease-modifying treatments for Parkinson’s, there are
“many challenges that need to be overcome before stem cell-based cell
replacement therapies for Parkinson’s disease are a reality. Work is still
needed to generate robust cells, in both quality and quantity, that can also
survive and function appropriately in a host brain. Although ES (and now iPS)
cells hold great potential, we do not yet know which stem cell type ultimately
holds the greatest promise.”
The authors of a commentary
published in the Journal of Parkinson’s Disease propose five key questions that
they say should be addressed as the clinical trial announced by
California-based biotech company International Stem Cell Corporation
(ISCO) begins.
ISCO announced on March 7 that it
is now enrolling patients in the Phase 1 trial of the company’s proprietary
ISC-hpNSC, which consists of a highly pure population of neural stem cells
derived from human parthenogenetic stem cells manufactured under cGMP
conditions that have undergone stringent quality control measures and are clear
of any microbial and viral contaminants.
They report that preclinical
studies in rodents and non-human primates have shown improvement in Parkinson’s
disease symptoms and increase in brain dopamine levels following intracranial
administration of ISC-hpNSC, which provides neurotrophic support and cell replacement
to the dying dopaminergic neurons of the recipient Parkinson’s brain. ISCO says
ISC-hpNSC are safe, well tolerated, and do not cause adverse events such as
dyskinesia, systemic toxicity or tumors in preclinical models, and that it
believes ISC-hpNSCmay have broad therapeutic applications for many neurological
diseases affecting the brain, the spinal cord and the eye.
The clinical trial is to be
conducted at Royal Melbourne Hospital in
Australia. ISCO says the Melbourne Health Human Research Ethics Committee
(HREC) has granted its approval of the Phase 1 clinical trial in patients with
moderate to severe Parkinson’s disease. This approval clears the study’s
initiation at the Royal Melbourne Hospital.
ISCO describes the Phase 1
clinical study as a dose escalation safety and preliminary efficacy study of
ISC-hpNSC, intracranially transplanted into patients with moderate to severe
Parkinson’s disease. The open-label, single center, uncontrolled clinical trial
will evaluate three different dose regimens of 30,000,000 to 70,000,000 neural
cells. Twelve participants with moderate to severe Parkinson’s disease
will be treated. Following transplantation, the patients will be monitored for
12 months at specified intervals to evaluate the safety and biologic activity
of ISC-hpNSC. PET scans will be performed at baseline as part of the screening
assessment, and at 6 and 12 months after surgical intervention. Clinical
responses compared to baseline after the administration of ISC-hpNSC will be
evaluated using various neurological assessments such as Unified Parkinson
Disease Rating Scale (UPDRS), Hoehn and Yahr, and other rating scales.
Russell Kern, Ph.D., executive vice
president and chief scientific officer of ISCO, said in a
release that “Enrollment in this trial is an important milestone. Promising
preclinical results support our expectation that ISC-hpNSC will bring a
long-needed solution for patients suffering from Parkinson’s disease. The
ability of our approach to replace and protect dopaminergic neurons and restore
neural function offers significant potential benefit to patients. We look
forward to preliminary clinical data in [the fourth quarter] of 2016.”
The Journal of Parkinson’s
Disease research Open Access article, titled “Are Stem
Cell-Based Therapies for Parkinsons Disease Ready for the Clinic in 2016?” co-authored
by Roger A. Barker, Malin Parmar, Agnete Kirkeby, Anders Bjorklund, Lachlan
Thompson, and Patrik Brundin, representing neuroscience research institutions
in the U.K., Sweden, Australia, and Michigan, observe that based on discussions held by a global collaborative initiative
on translation of stem cell therapy in Parkinsons disease, they have
arrived at a set of five key questions they believe should be addressed before
any stem-cell-based trial in Parkinson’s disease is done:
1) What is being transplanted,
and what is the proposed mechanism of action?
2) What are the pre-clinical
safety and efficacy data supporting the use of the proposed stem cell product?
3) Can arguments concerning
ethics, risk mitigation, or trial logistics outweigh concerns regarding the
expected efficacy of the cell and constitute a primary justification for
choosing one cell type over another in a clinical trial?
4) What is being claimed
regarding the potential therapeutic value of the stem cell-based therapy —
better control of symptoms or a cure?
5) What is the regulatory oversight
of the trial and is it guided by input from experts in the field?
In their article, the co-authors
first review a short history of cell therapy associated with Parkinson’s
disease and briefly describe the cutting-edge science regarding human stem
cell-derived dopamine neurons for use in any patient trial. With this
background information as a foundation, they then discuss each of the key
questions in relation to the ISCO trial and critically assess whether the time
is ripe for clinical translation of parthenogenetic stem cell technology in
Parkinson’s disease.
The authors observe that with
stem cell-based therapies now approaching the clinical trial stage in a number
of centers, active groups in the field have established a global collaborative
stem cell therapy advocacy initiative called G-Force PD
to collaborate on translation of laboratory findings to trials in order to
ensure optimal progress from experimental results toward the clinic. The aim of
the consortium is to define criteria by which to gauge their own progress
toward the clinic, while ensuring that all steps are conducted to the
highest standard and that the trials are not initiated prematurely.
For example, how does ISCO’s
clinical transplantation trial in Parkinson’s fare in light of the criteria
defined by the G-Force-PD consortium? In their article, the authors discuss
publicly available information regarding the ISCO trial, expressing some
concern regarding missing or incomplete information available from ISCO, noting
in particular there are concerns that the cell types being transplanted may not
function as desired; that supporting safety and efficacy data have not been
made public; and that the G-Force PD consortium also suggests the length of
follow-up in the ISCO trial may not be sufficient.
They acknowledge that “while
early claims suggesting the possibility of a cure had been made,” ISCO has now
taken what they deem is a “more measured position regarding potential
benefits.”
Nevertheless, the authors caution
that exaggerated claims pertaining to stem cell therapy are all too common in
the field given the regulatory hurdles, commercial interests, and personal
ambitions of participants in early-stage clinical trials. They divide their
discussion into five sections responding to each of the questions they’ve have
posed.
In their concluding remarks, the
Journal of Parkinson’s Disease article authors observe that as the ability of
scientists to make authentic midbrain dopaminergic neurons from stem cell
sources improves, so does the reality of a first in human clinical trials on
patients with Parkinson’s. And while that’s an exciting prospect, they contend
it’s one that should only be undertaken after all necessary pre-clinical data
and regulatory approvals have been obtained and verified, and criteria for
moving those cells to trials are fully resolved and met, criteria that are
currently a major focus of the GForce-PD consortium.
They observe: “Only too often are
exaggerated claims made, based on limited pre-clinical data and a desire to
pass the financial and regulatory hurdles needed to get to clinic, sometimes
driven by personal ambitions along with financial and commercial interests.”
“Many PD patients and their
families have questioned whether they should try to sign up for such a study.
As with many such exiting news items, however, one should also react with
caution, especially since the outcome of this trial can affect the development
of other stem cell programs moving toward clinical trials,” explains the
article’s lead author, Roger A. Barker,
Ph.D., of the John van Geest Centre for Brain Repair, Department of Clinical Neurosciences,
at the University of Cambridge in England, in a news release.
Barker noted it is timely to
provide insights into how the opportunities provided to Parkinson’s patients in
the ISCO trial and similar trials should be evaluated, maintaining that without
such insight, the patient community is left trying to interpret complex
scientific issues on its own, and will be unable to make informed decisions
about whether they should try to participate in the planned trials.
With the reality of the first
human clinical trial in patients with PD upon us, says co-author and Journal of
Parkinson’s Disease Editor-in-Chief Patrik Brundin, M.D., Ph.D., who
is also director of the Center for Neurodegenerative Science at the Van Andel Research Institute in Grand Rapids Michigan,
“This is an exciting
prospect but should only be undertaken when all the necessary pre-clinical data and
regulatory approvals have been obtained and verified and the criteria for
moving those cells to trials fully resolved and met. Acting prematurely has the
potential not only to tarnish many years of scientific work, but can threaten
to derail and damage this exciting field of regenerative medicine. Hopefully,
in 2016, we are ready to take a more careful approach as we strive to repair
the PD brain with stem cell-based therapies, avoiding many of the mistakes that
have dogged this field over the last three decades.”
http://parkinsonsnewstoday.com/2016/03/31/parkinsons-disease-stem-cell-therapies-finally-ready-clinical-trials-depends-say/
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