This roundup of recent amyotrophic lateral sclerosis (ALS) research and clinical trials news includes:
Neuralstem phase 1 trial results published
Update (April 7, 2014): A final, complete report on the phase 1 clinical trial of NSI-566 spinal cord-derived neural stem cells in people with ALS was published in the March 2014 issue of the journal Annals of Neurology. The paper can be read via the journal's website without charge. A March 17, 2014, press release from Neuralstem Inc. summarizes the paper and contains the following statement from neurologist Jonathan Glass, an investigator on this study and director of the MDA ALS Center at Emory University in Atlanta: "The completion of phis phase 1 study is a major milestone for the testing of intraspinal stem cell therapy for ALS. We have now shown that the procedure is safe for both lumbar [lower back] and cervical [neck region] injections, allowing us to move forward with an aggressive program to test whether this treatment will improve the coruse of disease for patints with ALS."
The report includes the results from 15 people with ALS, 12 of whom received one set of intraspinal stem cell injections and three of whom received two sets of injections. The trial demonstrated that the injection procedure appears safe, well-tolerated and feasible. Although it was not designed to show efficacy, the trial raises the possibility that intraspinal stem cell transplantation of stem cells in patients with no bulbar (speaking and swallowing) symptoms who are early in the course of their disease could slow disease progression or even allow for functional improvement. A phase 2 trial (number NCT01730716 on ClinicalTrials.gov) is open to participants by invitation only.
Results for a completed phase 1 clinical trial to test NSI-566 spinal cord-derived neural stem cells in people with ALS were published online Sept. 5, 2013, in Neurosurgery. As previously reported, the treatment and the surgical delivery method used to administer it were found to be safe and well-tolerated. In addition, trial participants who had limb-onset (as opposed to bulbar-onset) ALS and who received the cells earlier rather than later in their disease course had better outcomes.
The stem-cell-based treatment, under development by Neuralstem Inc., was administered 18 times to 15 trial participants. (Three participants who were treated in an earlier phase were allowed by the U.S. Food and Drug Administration to return later in the trial.)
A phase 2 trial of Neuralstem's NSI-566 stem cells in ALS is ongoing. For information, see Dose Escalation and Safety of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, or enter NCT01730716 into the search box at ClinicalTrials.gov.
Experimental therapy targets SOD1 gene
A one-time treatment with an experimental therapy designed to block production of SOD1 protein was associated with increased survival time in two different mouse models of ALS. Mutations in the SOD1 gene are a known cause of familial ALS; faulty SOD1 protein also has been implicated in some sporadic ALS. Improved survival was observed in both mild- and severe-ALS mouse models, whether the treatment was administered before disease onset or after symptoms began.
Further studies in a non-human primate model showed that the treatment decreased SOD1 protein levels in the spinal cord by 87 percent.
The researchers blocked production of the SOD1 protein using a technology known as short hairpin RNA, or shRNA. These single strands of RNA are designed in the lab to seek out specific sequences found in the human SOD1 gene, latch onto them and block the gene activity that allows for production of SOD1 protein.
The researchers, led by Don W. Cleveland at the University of California, San Diego, in La Jolla, and Brian K. Kaspar at Nationwide Children's Hospital College of Medicine in Columbus, Ohio, published their findings online Sept. 6, 2013, in Molecular Therapy. See also, a Sept. 9, 2013, Nationwide Children's press release: Therapy Slows Onset and Progression of Lou Gehrig's Disease, Study Finds.
TDP43 and behavior
Protein clumps (aggregates) containing TDP43 protein are found in the motor neurons of most people with ALS and in some people with frontotemporal dementia (FTD). Mouse models engineered to over-produce mutant human TDP43 protein have neurodegeneration and reduced life span. David X. Medina, Miranda E. Orr, and Salvatore Oddo, at University of Texas Health Science Center at San Antonio, found that these mice also develop deficits in cognition, motor performance and coordination that are associated with aggregates containing TDP43 protein, decreased levels of normal TDP43 protein and loss of connections (synapses) where nerve cells interact with other cells.
The team, which published its results online Aug. 15, 2013, in Neurobiology of Aging, says its findings "provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents," in TDP43-associated diseases.
TDP43 and body fat
TDP43 — a protein associated with nearly all ALS — may play an important role in regulating energy metabolism, reports a research team led by Jeffrey Elliott at the University of Texas Southwestern Medical Center in Dallas.
It's been shown that mice with no TDP43 die in the early embryonic stage, while mice with decreased levels of the protein show weight loss, fat depletion and rapid death.
Elliott, and colleagues, found that mice engineered to have too much TDP43 protein show increased fat mass and a corresponding decrease in lean body mass. In addition, the mice have abnormalities in skeletal muscle glucose (sugar) handling.
The team noted that loss of weight and muscle mass are common in ALS, where they are associated with decreased survival time, and suggest it may be worth investigating whether these changes are a direct consequence of altered TDP43 function in the disease.
The team published its findings Aug. 13, 2013, in PLoS One. See TDP43, an ALS Linked Protein, Regulates Fat Deposition and Glucose Homeostasis.
Respiratory care in ALS
Noninvasive ventilation (NIV) has been shown to improve survival and quality of life in ALS. "Therefore, while the optimal timing of NIV initiation is an important consideration, it is not as important as ensuring that those who qualify for it, based on current criteria, are offered the intervention," writes Loutfi S. Aboussouan and Eduardo Mireles-Cabodevila, at the Respiratory Institute, Cleveland Clinic in Cleveland, Ohio. However, they note, "only 21 percent of patients with ALS receive NIV when they would qualify for it, based on existing guidelines."
Aboussouan and Mireles-Cabodevila address these and other respiratory care considerations — including questions about placement and use of tracheostomy — in their review, Respiratory Support in Patients with Amyotrophic Lateral Sclerosis. They stress that people with progressive neuromuscular diseases such as ALS are living longer, with a better quality of life. "While there has been substantial progress, until more definitive treatments for ALS are found, much more remains to be done in the supportive care of our ALS patients."