StemCells, Inc. Presents Two-Year Pelizaeus-Merzbacher Disease Data Suggesting Increased Myelination of Nerves


StemCells, Inc. has presented data of their two-year follow-up of patients with Pelizaeus-Merzbacher disease (PMD) who were treated with the Company’s proprietary HuCNS-SC cells. HuCNS-SC is a purified human neural stem cell line, and these neural stem cells can differentiate into a very wide variety of cell types of the nervous system, including different types of neurons and glial cells.

PMD is an inherited condition that involves the central nervous system. It is one of a group of genetic disorders called “leukodystrophies,” which all have in common degeneration of myelin. Myelin covers nerves and protects them, and promotes the efficient transmission of nerve impulses. PMD is caused by an inability to synthesize myelin (dysmyelination). Consequently, PMD individuals have impaired language and memory abilities, and poor coordination. Typically, motor skills are more severely affected than intellectual function; motor skills development tends to occur more slowly and usually stops in a person’s teens, followed by gradual deterioration.

Since PMD is an X-linked genetic disease, it is far more prevalent in males, and an estimated 1 in 200,000 to 500,000 males in the United States have PMD, but it rarely affects females.

Mutations in the PLP1 gene usually cause PMD. The PLP1 gene encodes proteolipid protein 1 and a modified version (isoform) of proteolipid protein 1, called DM20. Proteolipid protein 1 and DM20 are primarily in the central nervous system and are the main proteins found in myelin. The absence of proteolipid protein 1 and DM20 can cause dysmyelination, which impairs nervous system function and causes the signs and symptoms of Pelizaeus-Merzbacher disease.

In this trial, PMD patients were injected with HuCNS-SC cells. In this report, magnetic resonance imaging (MRI) studies were used to determine the amount of myelin that insulated particular nerves in the central nervous system. MRI examination of the patients revealed evidence of myelination that is more pronounced that what was seen in the one year post-transplantation exams. The gains in neurological function reported after one year were maintained, and there were no safety concerns.

Patients with PMD have insufficient myelin in the brain and their prognosis is very poor, usually resulting in progressive loss of neurological function and death. The neurological and MRI changes suggest a departure from the natural history of the disease and may represent signals of a positive clinical effect. These data were presented by Stephen Huhn, MD, FACS, FAAP, Vice President, CNS Clinical Research at StemCells, Inc., at the 2013 Pelizaeus-Merzbacher Disease Symposium and Health Fair being held at Nemours/Alfred I. duPont Children’s Hospital in Wilmington, Delaware.

“We are encouraged that the MRI data continue to indicate new and durable myelination related to the transplanted cells and that the data is even stronger after two years compared to one year,” said Dr. Huhn. “Even in the context of a small open-label study, these MRI results, measured at time points long after transplantation, make an even more convincing case that the HuCNS-SC cells are biologically active and that their effect is measurable, sustainable, and progressive. Our challenge now is to reach agreement with the FDA on how best to correlate changes in MRI with meaningful clinical benefit, as this will be a critical step in determining a viable registration pathway for PMD.”

The Company’s Phase I trial was conducted at the University of California, San Francisco, and enrolled four patients with “connatal” PMD, which is the most severe form of PMD. All four patients were transplanted with HuCNS-SC cells, and followed for twelve months after transplantation. During the year of post-transplantation observation, the patients underwent intensive neurological and MRI assessments at regular intervals. Since none of the patients experienced any serious or long-lasting side effects from the transplantation, the results of this Phase I trial indicate a favorable safety profile for the HuCNS-SC cells and the transplantation procedure.

Data from MRI analyses showed changes consistent with increased myelination in the region of the transplantation. This increased myelination progressed over time and persisted after the withdrawal of immunosuppressive drugs nine months after transplantation. These results support the conclusion of durable cell engraftment and donor cell-derived myelin in the transplanted patients’ brains. Also, routine neurological exams revealed small but consistent and measurable gains in motor and/or cognitive function in three of the four patients. The fourth patient remained clinically stable. These Phase I trial results were published in October 2012 in Science Translational Medicine, the peer review journal of the American Association for the Advancement of Science. Upon completion of the Phase I trial, all four patients were enrolled into a long-term follow-up study, which is designed to follow the patients for four more years.

The Transformation of Ordinary Skin Cells into Functional Brain Cells


A paper in Nature Biotechnology from research groups at Case Western Reserve School of Medicine describes a technique that directly converts skin cells to the specific type of brain cells that suffer destruction in patients with multiple sclerosis, cerebral palsy, and other so-called myelin disorders. This particular breakthrough now enables “on demand” production of those cells that wrap or “myelinate” the axons of neurons.

Myelin is a sheath that wraps the extension of neurons called the axons. Neurons are the conductive cells that initiate and propagate nerve impulses. Neurons contain cell extensions known as axons that connect with other neurons. The nerve impulse runs from the base of the cell body of the neurons, down the axon, to the neuron to which it is connected. An insulating myelin sheath that surrounds the axon increases the speed at which nerve impulses move down the axon. When this myelin sheath is damaged, nerve impulse conduction goes awry as does nerve function. For example, patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed are not replaced.

neuron

The new technique discussed in this Nature Biotechnology paper, directly converts skin cells called fibroblasts, which are rather abundant in the skin and most organs, into oligodendrocytes, the type of cell that constructs the myelin sheath in the central nervous system.

Oligodendrocyte

“Its ‘cellular alchemy,'” explains Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”

Tesar and his group used a technique called “cellular reprogramming,” to manipulate the levels of three naturally occurring proteins to induce the fibroblasts to differentiate into the cellular precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).

OPCs

Led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, Tesar’s research team rapidly generated billions of these induced OPCs (called iOPCs). They demonstrated that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.

Demyelinating diseases damage the oligodendrocytes and cause loss of the insulating myelin coating. A cure for these diseases requires replacement of the myelin coating by replacement oligodendrocytes.

Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but have distinct limitations.

“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explains co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”

Even though this initial study used mouse cells, the next critical next step is to demonstrate feasibility and safety of human cells in a laboratory setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.

“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” says Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”