The first nine participants in a phase 1 (safety and feasibility) trial of neural stem cell transplantation in amyotrophic lateral sclerosis (ALS) remain alive, and there were no unresolved serious adverse reactions to the procedure, according to biotechnology company Neuralstem on April 12, 2011. (See the Neuralstem press release, Dr. Eva Feldman, Principal Investigator, Presents Interim Safety Results for Neuralstem ALS Trial.) The most common adverse events were temporary pain near the injected area and problems related to the immune system suppression used in this study.
Trial participants received injections directly into their lumbar spinal cord of neural stem cells derived from a human fetus. The first six were unable to walk when they entered the trial; the last three were able to walk. The three patients who entered the trial able to walk have remained able to do so since the procedure.
If approved by the U.S. Food and Drug Administration (FDA) and the trial's safety monitoring board, the transplantation trial will begin injecting into the cervical (neck area) spinal cord in ALS patients in the summer of 2011.
Eva Feldman, principal investigator for the trial and an unpaid Neuralstem consultant, presented these interim safety data at the AAN meeting April 11.
Anne-Marie Wills, an MDA grantee who is studying nutrition and ALS at Massachusetts General Hospital in Boston, discussed the relationship between body mass index (BMI) and survival in ALS on April 13. Her findings suggest that being slightly overweight or even moderately obese is an advantage for survival with this disease.
Her research, based on data from 776 people, has found that there is a survival advantage in people with ALS with BMIs in the overweight (25-29.9) and moderately obese (30-34.9) categories. Those in the moderately obese category survived the longest. Those classified as underweight (BMI less than 18.5), normal weight (BMI 18.5-24.9) or morbidly obese (BMI more than 35) did not fare as well.
BMI is a measure of body "fatness" and can be calculated by multiplying one's weight in pounds times 4.88 and dividing the result by one's height in feet squared. The body mass index calculator provided by the National Institutes of Health will do the math for you.
Wills says her data show that the survival advantage seen in people with higher BMIs is not due exclusively to less advanced disease, suggesting that BMI alone is an independent predictor of survival time and that modifying it might affect disease progression.
For more on nutrition and ALS, see ALS Experts: Keep the Weight On; Eat, Drink and Be Healthy is the Motto in ALS and an MDA webinar featuring Anne-Marie Wills called "The Importance of Nutrition for Individuals with ALS" at Educational Presentations — Public Webinar Series.
An April 13 presentation by Adriano Chio from the University of Torino (Italy) raised the question of whether ALS patients who participate in clinical trials are representative of the ALS population as a whole. In his study, conducted in Italy, participants in ALS clinical trials were, on average, younger, had a longer onset-to-diagnosis time, were more likely to have spinal-onset disease, to be men, and to have familial ALS than were those in the general ALS population. Chio suggested that clinical trial entry criteria may need to be altered to allow inclusion of a larger portion of patients.
Editor's note: There's a caveat to this concept, in that clinical trials are carefully controlled experiments to see whether a new treatment works better than an old one or than a placebo. In any experiment, one wants to limit the number of factors that may affect the outcome, which translates into narrow inclusion criteria for most trials. For more about clinical trial participation, see Being a Co-Adventurer.
Elisa Canu provided data on April 13 from a research team based in Milan, Italy, that found evidence of altered activity in the brain's cognitive centers in people with ALS who did not have any overt signs of cognitive abnormality.
The team studied 16 people with sporadic ALS and no cognitive problems and 15 people without any known disease. Using functional magnetic resonance imaging (MRI), they found that those with ALS had less connectivity in the front part of the brain and more in the regions behind the front part than healthy people did, a pattern the researchers have speculated may reflect attempted compensation for damage to the front part of the brain. They note that the same pattern is seen in people with frontotemporal dementia (FTD).
Editor's note: Caveats are 1) the study was small and 2) it isn't known whether the MRI changes predict a change in cognitive functioning.
On April 13, Carmel Armon from Baystate Medical Center in Springfield, Mass., presented a review of medical literature published since 1980 that addressed the question of whether trauma to the head contributes to ALS risk. The investigators concluded that the literature does not support an association between head injury and ALS development.
Various researchers have speculated for years about the possible role of head trauma in ALS causation. The debate was reignited in August 2010, after the authors of a very small study suggested that head injury in professional athletes could be a contributor to the disease. (See ALS Experts Urge Caution Regarding Head Injury Findings.)
Armon said flatly that the issue does not merit further investigation.
Research from the laboratory of Teepu Siddique at Northwestern University in Chicago has shown that a gene that codes for the p62 protein can, when flawed, cause ALS. A representative from Siddique's group gave this presentation on April 14.
The investigators screened 340 people with familial ALS and 206 with sporadic ALS and found mutations in the p62 gene in seven people with familial and eight with sporadic disease. Mutations in p62 were not seen in any of the more than 700 unaffected people whose DNA was screened.
The p62 gene had been selected for screening because the p62 protein has been found in aggregates (clumps) in ALS-affected spinal motor neurons, along with FUS and TDP43 protein molecules; and FUS and TDP43 gene mutations are known causes of ALS.
A graduate student from the laboratory of MDA grantee Robert Baloh at Washington University in St. Louis reported April 14 on the group's studies in a TDP43 mouse model of ALS. This research group has created mice in which an ALS-causing TDP43 mutation can be turned on and off (an "inducible" model) so that its effects can be studied in different tissues and at different time points.
The researchers have found that mutant TDP43 protein has to reach three times its normal level before the mice start showing degeneration of nerve cells. They also found that, once mutant TDP43 reaches this high level, the amount of normal TDP43 in the mouse is significantly reduced, indicating that the ALS-like disease in the mice may be a result of a toxic gain of function of the mutant TDP43 protein as well as a loss of function of the normal TDP43 protein. Much work has been done and remains to be done regarding the role of TDP43 in ALS.
Takanori Yokota from Tokyo Medical and Dental University presented his research team's studies of a monkey model of TDP43-related ALS on April 14. The monkey appears to be a better model of human ALS than the TDP43 mouse model, both in terms of clinical manifestations of the disease and cellular changes.
A member of the laboratory of Stanley Appel, an MDA research grantee at Methodist Neurological Institute in Houston, gave a presentation April 14 showing that regulatory T cells suppress activation of two types of cells (microglia and effector T cells) that contribute to harmful inflammation in the nervous system in ALS mice. These mice had an ALS-like disease because of a mutation in the SOD1 gene. The findings suggest that increasing the level or activity of regulatory T cells could be therapeutic in ALS.
Koji Yamanaka from the Riken Brain Science Institute, located near Tokyo, presented his laboratory's findings on April 14 on the apparent benefits of certain activities of the immune system in ALS SOD1 mice. Yamanaka's group has found that the innate immune response that works through a pathway known as TRIF is beneficial for this ALS mouse model and that eliminating it accelerated disease progression in these rodents.
For more about the immune system in ALS, see Immune System Modulator Heralds New Strategy in ALS Research, Disconnecting the Immune System, Blocking a Protein Extends Survival in ALS Mice, Immune system regulator shows safety in ALS, Examining the Role of Microglia in ALS, and ALS: Not Just About Motor Neurons Anymore.