Trials, U.S.: Amyotrophic Lateral Sclerosis
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Clinical Trials, U.S.: Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating neurodegenerative disorder characterized by rapidly progressive weakness due to degeneration of motor neurons in the brain cortex, brain stem, and spinal cord. Patients can present with a variety of symptoms, usually starting with signs of muscle weakness and/or atrophy in the upper or lower limbs. Patients may also present with “bulbar” onset, referring to the functions of the medulla oblongata, such as trouble with speaking or swallowing or difficulty with tongue movement. Over time, patients experience progressive difficulty with voluntary movement to eventual paralysis and death within an average of three to five years from disease onset.
Treatments for ALS have been limited due to the diverse nature and unknown etiology of the disease. Riluzole (Rilutek) is the only FDA-approved treatment known to improve survival in ALS patients, but only for a period of several months. Much of this difficulty in finding treatment relates to the various etiologies and heterogeneity that exists within ALS. In recent years, much interest has been divested into the use of human pluripotent stem cells for the treatment of ALS. While the initial idea was to use the pluripotent stem cells to replace lost motor neurons in ALS, this idea proves impractical given the long-distance projections and complicated functional connections that these new stem cell motor neurons would need to make in order to replace their predecessors. Another more feasible option would be to use the pluripotent stem cells to re-create support cells in the neuronal environment, nourishing already existing motor neurons to thrive and possibly detoxifying the environment to prevent further cell death.
Support cell types in the nervous system can be generated from other tissues such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Mesenchymal stem cells can be derived from existing connective tissue such as bone marrow, cartilage cells, and fat cells, as well as from umbilical cord tissue. Neural stem cells can be derived from the fetal brain. Preclinical studies have shown the ability to use MSCs and NSCs to generate functional support cells to improve motor neuron survival in ALS models. The hope is to determine the safety and efficacy of using mesenchymal and neural stem cell transplantation into patients with ALS and maximize the therapeutic benefit achievable with such treatment.
U.S. Clinical Trials Studies
Within the United States, there is more interest surrounding the use of neural stem cells for the treatment of ALS than there is in the use of MSCs. The first Phase I in-human trial of spinal-derived stem cells transplanted into the spinal cord of patients was completed by Neuralstem Inc. at Emory University. From 2010 to 2013, the study utilized a microsurgical transplantation device to transplant human spinal cord–derived NSCs into the spinal cord of 15 ALS patients. The study utilized the Spinal Cord Delivery Platform and Floating Cannula patented by Neuralstem and designed by Neuralstem ALS neurosurgeon, Nicholas M. Boulis, MD. The platform is designed to mount on the backs of patients to deliver a precise dosage of cells at a precise depth within the grey matter of the patient’s spinal cord. Neuralstem combined the use of its Spinal Cord Delivery Platform and Floating Cannula with the use of its patented NSI-566 neural stem cells, which has been shown in animal models to prevent spinal motor degeneration in ALS mice.
The Phase I study (NCT01348451) was done in a risk escalation design, with patients starting with either unilateral or bilateral lumbar transplantation and moving on to unilateral or bilateral cervical transplantation. The study found no long-term surgical complications and no significant adverse side effects. The ALS patients also gave no indications that the disease progression had accelerated after transplantation. Therefore, the technique and surgical unilateral and bilateral transplantation of NSC cells in this trial was deemed safe and well-tolerated.
In September 2013, a Phase II study (NCT01730716) was initiated to further test the safety and maximum dose profile of this specific surgical technique and transplantation, making it the first clinical trial in the United States to move beyond Phase I for the treatment of ALS using stem cell technology. Another Phase I patient safety study using MSC intraspinal transplantation was completed by the Mayo Clinic from 2010 to 2011 (NCT01142856, NCT01609283). In their study, Anthony Windebank et al. isolated autologous MSCs from adipose tissue and injected them via lumbar puncture into the cerebrospinal fluid of patients with ALS. No study results have been published to date.
TCA Cellular Therapy in Covington, Louisiana, is also currently running a Phase I safety trial (NCT01082653) using autologous bone marrow–derived MSC stem cell transplantation for ALS treatment, though no results have been published for this study either.
Another approach that has been extensively studied in recent years is the process of culturing human fetal cortex–derived neural cells as 3-dimensional aggregates termed “neurospheres” in the presence of mitogens and passaged via a mechanical chopping method. The cells differentiate into astrocytes and some neurons, but not oligodendrocytes. Because of this limited differentiation potential, these cells are bipotent neural progenitor cells (NPCs). Human NPCs (hNPCs) can be genetically engineered to secrete neurotrophic factors in vivo. Glial cell–derived neurotrophic factor is viewed as especially interesting, given its ability to enhance survival of motor neurons in vitro and in vivo.
Clive Svendsen et al. at Cedars-Sinai have studied the unilateral transplantation of hNPCs secreting GDNF in the lumbar spinal cords of rats expressing the SOD1G93A mutation associated with ALS. This study found significantly greater numbers of surviving motor neurons in transplanted rats. However, there was no functional benefit on motor behavior or neuromuscular innervation. Based on these studies, hNPCs expressing GDNF are being evaluated for further clinical trials.
Leslie Suen
Pablo Avalos
Doniel Drazin
Cedars-Sinai Medical Center
See Also: Clinical Trials Outside the United States: Amyotrophic Lateral Sclerosis; Mayo Clinic; Neuralstem, Inc.
Further Readings
Beksac, Meral. Bone Marrow and Stem Cell Transplantation. New York: Springer, 2014.
Blanquer, M., et al. “Neurotrophic Bone Marrow Cellular Nests Prevent Spinal Motoneuron Degeneration in Amyotrophic Lateral Sclerosis Patients: A Pilot Safety Study.” Stem Cells, v.30/6 (June 2012).
Svendsen, Clive, et al. “The Past, Present, and Future of Stem Cell Clinical Trials for ALS. Experimental Neurology (in press).
Clinical Trials, U.S.: Batten Disease
Clinical Trials, U.S.: Batten Disease
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Clinical Trials, U.S.: Batten Disease
Batten disease, a rare, fatal autosomal recessive disorder of the nervous system that begins in early childhood, also called Spielmeyer-Vogt-Sjögren-Batten disease, was named after British pediatrician Frederick Batten, who first described the condition in 1903 as the immature form of neuronal ceroid lipofuscinosis (NCL). The disorder consists in the deficiency of the TPP1 enzyme following mutations in the CLN2 gene. Today, a great number of physicians associate the term Batten disease
