- A variant in the gene for the PGC1-alpha protein appears to modify onset and survival in amyotrophic lateral sclerosis, but only in men.
- Treatment with stem cells engineered to produce either of two proteins — GDNF or VEGF — slowed disease progression in a rat model of ALS; treatment with stem cells engineered to produce both proteins correlated with a greater effect.
- Treatment of cells carrying an ALS-causing gene mutation with genes called PRDX3 or NRF2 reduced oxidative stress and improved survival; however, mouse experiments did not show benefit.
Identification of the biological mechanisms that underlie amyotrophic lateral sclerosis (ALS) may provide scientists with important clues about the disease that may be used to identify biomarkers and potential biological targets for therapy development.
A male-specific ALS disease modifier?
A variant in the gene for the PGC1-alpha protein appears to modify onset and survival in ALS, but only in men, a multinational research team has reported.
The PGC1-alpha protein has roles in numerous cellular processes, including formation of new blood vessels and a cellular “garbage-disposal system” called autophagy.
Patrick Weydt at Ulm University (Germany), and colleagues studied DNA from 590 people with sporadic ALS in Germany, and from a second group of 464 people with ALS in Sweden.
- In the German group, the variant was associated with a younger age at symptom onset (an average of four years younger than those without the variant) and a younger age at death (an average of eight years younger).
- In the Swedish group, the variant also correlated with a younger age at death (3.3 years earlier average age of death) and a disease course that was 50 percent shorter, on average, than those without the variant (1.5 years versus 3.1 years).
- In both groups, the effects were limited to men; no effects from the PGC1-alpha gene variant were seen in women.
In further studies conducted in a mouse model of ALS, the researchers showed that deficiency of full-length PGC1-alpha protein leads to a significantly earlier age of disease onset and a slightly shortened survival time in male, but not female, mice. The reason for the gender difference in humans and mice is unknown.
The investigators also noted that the modifier effect on ALS onset and survival was much more pronounced in humans than in mice, for reasons that are not clear.
The team published its findings online May 12, 2013, in Human Molecular Genetics. See the full article: PGC1-alpha is a Male-Specific Disease Modifier of Human and Experimental Amyotrophic Lateral Sclerosis.
GDNF and VEGF work best in combination
Two proteins — glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) — had a greater effect on slowing disease progression when administered in combination to rats with a disorder mimicking ALS than did either protein alone, reports a research team based at institutions in the United States and Switzerland.
The team, led by Masatoshi Suzuki at the University of Wisconsin, Madison, engineered stem cells derived from human bone marrow to secrete GDNF, VEGF, or one of two other protein growth factors: insulin-like growth factor 1 (IGF1) and brain-derived neurotrophic factor (BDNF). These were then injected into three different muscle groups in the rats.
Stem cell delivery of IGF1 or BDNF had no effect on the rats’ disease course. However, researchers found that stem cells delivering GDNF or VEGF prolonged survival and slowed the loss of muscle function in the rats. When the stem cells were engineered to deliver GDNF and VEGF together, there was an even greater effect.
On the other hand, rats who did not receive treatment survived an average of 173 days:
- rats treated with stem cells producing GDNF survived an average of 191 days, and those treated with VEGF survived an average of 186 days; and
- rats treated with stem cells producing both GDNF and VEGF survived an average of 201 days, a significant increase of 28 days compared to untreated rats.
In addition, both GDNF and VEGF had a protective effect on neuromuscular junctions — where nerve and muscle fibers interact — and motor neurons.
The team published it findings May 28, 2013, in Molecular Therapy. See Synergistic Effects of GDNF and VEGF on Lifespan and Disease Progression in a Familial ALS Rat Model (abstract).
Antioxidant gene transfer a potential therapeutic strategy in ALS
When cells that have an ALS-causing mutation are treated with either of two genes — PRDX3 or NRF2 — the result is reduced oxidative stress, a type of cell damage thought to play a role in the disease, reports a multinational research team based in Germany, Greece, Saudi Arabia and the United Kingdom.
Mimoun Azzouz at the University of Sheffield (United Kingdom) and King Abdulaziz University (Saudi Arabia), and colleagues, treated ALS-affected cells with these antioxidant (oxidative stress-reducing) genes and measured levels of oxidative stress in the treated versus untreated cells.
In experiments performed in a cellular model of ALS, treatment with the antioxidant genes (which were engineered to overproduce the PRDX3 or NRF2 proteins) was associated with a significant decrease in oxidative stress levels. The number of surviving cells increased by 30 percent in both cases.
However, when the investigators injected the genes into the muscles of a mouse model of ALS, they saw no benefit. There was no significant effect on neurological score, age of onset, disease onset, progression or survival.
Investigators say they don't think many of the therapeutic genes reached the nervous system in the mice after injection into muscle tissue and that a more effective delivery approach might yield a better result.
The team published its findings June 4, 2013, in Molecular Therapy. See Viral Delivery of Antioxidant Genes as a Therapeutic Strategy in Experimental Models of Amyotrophic Lateral Sclerosis (abstract).