ARTICLE IN BRIEF
In an animal model and a small open label trial, investigators were able to show proof of principle that human neural stem cells could safely be transplanted directly into the brains of four boys with a severe form of Pelizaeus-Merzbacher disease. MRI findings suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.
Results of a phase I study published in the Oct. 10 edition of Science Translational Medicine offer the first evidence to date that neural stem cells can safely engraft and successfully propagate when transplanted into the brains of patients with myelination disorders.
In the trial, conducted by researchers at the University of California, San Francisco (UCSF) and sponsored by the cells' developer, Stem Cells, Inc., a total of 300 million human central nervous system stem cells (HuCNS-SCs) per patient were injected into the frontal lobe white matter — the anterior and posterior frontal centrum semiovale or corona radiata — of four boys with the early onset, more severe — or connatal — form of Pelizaeus-Merzbacher disease (PMD), an X-linked autosomal dysmyelinating disorder.
In PMD, mutations on the proteolipid 1 (PLP1) gene disrupt the brain's ability to form myelin; in the connatal form, mutations that disrupt critical area of the PLP1 and DM20 (an isoform of PLP1) proteins lead to an early-onset form of the disease that is invariably fatal. Children with this disease progressively lose motor control and other function, and usually die by their mid-teens.
In the yearlong proof of principle trial, the four boys — two around a year old when the study began, one aged 3, and another 5 — received immunosuppression for nine months after receiving the stem cells, and were assessed at three-month intervals using serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, as well as high-angular resolution diffusion tensor imaging (DTI).
“We found evidence for durable engraftment of the neural stem cell transplants, even after immunosuppression was discontinued, and a favorable safety profile after one year,” said lead investigator David Rowitch, MD, PhD, chief of neonatology and professor of pediatrics and neurological surgery at UCSF. He noted that the safety findings are the most significant results of the study.
“If we'd found adverse safety consequences, it would have had a dampening effect on the entire field,” he said.
But at first, there was also no sign of myelination.
“We looked at the three-month scans and the six-month scans and said, ‘There's nothing going on here,’” said Dr. Rowitch. “But at about nine months post-transplant, we started to see small changes on T1- and T2-weighted MR imaging, and in DTI imaging, we saw the sorts of increases in fractional anisotropy over time that one would expect if there were myelin formation.”
“In a normal child's brain, you would expect to see about 10- to 15-percent increases in fractional anisotropy,” explained Nalin Gupta, MD, PhD, Dennis Bruce Dettmer endowed chair in pediatric neurosurgery and director of the Pediatric Neurological Surgery program at UCSF. “In these children, we saw around 6 percent, where usually with PMD you wouldn't expect to see any change at all over time.”
The findings aren't definitive, Dr. Rowitch cautioned. “We can't say for sure that this is myelin. Potentially some other cellular effects could give some of the changes we saw, but the data we have seems to point to durable engraftment and a prolonged biological effect a year after transplant. It's consistent with myelin formation in the transplanted parts of the brain that we don't see elsewhere.”
WHY PMD WAS CHOSEN FOR TRIAL
One of the reasons the severe form of PMD was chosen for this trial — aside from its inevitably progressive and fatal course, which makes it a more reasonable candidate for a highly experimental therapy than a more simply chronic, if progressive, myelin disorder like multiple sclerosis — was because it is a dysmyelinating disorder rather than a demyelinating one. Boys with PMD don't lose the myelin sheaths insulating their axons; they never develop them properly.
“We could not have distinguished donor-driven myelin from host myelin in a normal brain,” Dr. Rowitch said. “PMD supports ‘proof-of-concept’ because of the total absence of myelin. If there is new myelin in these boys' brains, we can better attribute it to the neural stem cells.”
The study was not designed to confirm efficacy, due to the lack of controls. But three of the four boys did show what the researchers characterized as modest improvements in some neurological functions. “These kids are severely disabled, unable to care for themselves, don't have fine motor movements, usually have difficulty controlling their heads, cannot walk, and often have tracheostomies,” explained Dr. Gupta. “But three of them showed improved head control, eye control and general motor function, and one is even starting to walk with a walker. This is unexpected in children with this condition.”
Dr. Rowitch urges against making too much of these particular results, because although PMD is considered to be ultimately neurodegenerative, it is not a straight downward trajectory — more like one step forward and three steps back. “In our study, no patients deteriorated and three had neurological gains. So what we can say is that the cells did not make them worse, and that is an important finding,” he said.
The next step, everyone interviewed here agreed, would be a phase 2 study of neural stem cell transplantation in a larger population of connatal PMD patients, around 20-40. (Families of the four patients in the original study have all given their consent to an ongoing four-year observational trial, as well.) Given the incidence of the disease — 1 in every 250,000 to 500,000 births — such a study might include international sites.
Pediatric neurosurgeon Stephen Huhn, MD, directs the preclinical and clinical development programs for CNS indications at Stem Cells, Inc., and said that the company is “very enthusiastic” about moving forward with such a trial. He won't commit to a definitive timeline, noting that any plans for a controlled phase 2 trial will involve extensive discussions with the Food and Drug Administration about trial design. “But we're very interested in moving this along as quickly as we possibly can,” he noted.
Stem Cells Inc. had a disappointment last year with a similar trial for neuronal ceroid lipofuscinosis (NCL, or Batten disease); on April 8, 2011, it announced that it would discontinue a phase Ib trial of stem cell therapy for Batten disease due to lack of patient accrual. But Dr. Huhn said that the circumstances for PMD are different.
“NCL patients are typically diagnosed later in the course of the disease, when they've already undergone significant loss of neurons and cerebral atrophy,” he said. “Identifying enough NCL patients as early in the course of the disease as we needed to would have taken a very long time, if it had even been possible at all. PMD, on the other hand, doesn't have that same delay in diagnosis. The symptoms and signs are so striking that a definitive diagnosis can be made much earlier, and we can enroll patients in a much more timely fashion.”
What about the study's implications for other myelination disorders, such as other leukodystrophies, transverse myelitis, certain forms of cerebral palsy, and ultimately the much more common multiple sclerosis?
“Each of those diseases could be an appropriate cell therapy target, but each has unique clinical and biological attributes that we have to consider,” Dr. Huhn said. “The fact that PMD is a dysmyelination disorder rather than demyelination means that the pathology is slightly different. But we now have human data that says this is possible. While MS is much more complex, because of the demyelinating and autoimmune component, it is on the horizon — something we can think about in terms we couldn't before.”
Dr. Huhn said that he prefers to be overcautious and avoid raising unrealistic expectations. “For that reason, I'm often accused of being understated. But as a pediatric surgeon, these findings are truly exciting; this is one of the first times that we've got a tool that might be a way to repair the central nervous system.”
Steven Goldman, MD, PhD, professor and emeritus chair of neurology at the University of Rochester School of Medicine and co-director of its Center for Translational Neuromedicine, who has published extensively in animal models on the use of a different cell-based treatment for myelination disorders — glial progenitor cells — praised the study for its care and comprehensiveness.
“They did get the field off the ground in a significant way,” he said. “The animal data has been out there for several years, but you need a commercial entity to really scale it up to put it into this kind of trial. Even with just four patients, a trial like this is a tremendous undertaking in terms of the requisite endpoints and surrogate data. A tremendous amount of work went into these four kids.”
But he's not certain that the MRI findings of myelination are as convincing as has been portrayed. “I think the jury's still out on that,” he said. “Looking at the images, I'm not yet convinced whether there's significant myelination. There are some small foci of signal change that may well represent remyelination but could also be local areas of glial proliferation.”