People affected by a rare, inherited form of dwarfism virtually never get diabetes or cancer, scientists have reported. Their findings may someday open up new ways to treat or prevent both conditions.

The scientists are Jaime Guevara-Aguirre, an Ecuadorean physician, and Valter Longo, a cell biologist from USC. They collaborated to study a cohort of about 100 Ecuadoreans that had Laron syndrome, an extremely rare condition caused by a gene mutation that prevents their bodies from responding properly to growth hormone.

Guevara-Aguirre had been following the cohort for more than 2 decades. He and Longo reviewed his notes and found exactly one nonfatal case of cancer and zero cases of diabetes. By comparison, the scientists’ review of 1,600 relatives, who also resided in Ecuador, revealed that 5% of them developed diabetes and 17% developed cancer. These incidence rates matched those found in the general population.

The absence of diabetes was particularly remarkable since the Laron cohort had higher obesity rates than their non-affected relatives, and obesity is a risk factor for the disease.

To figure out why Laron dwarfs almost never got diabetes or cancer, the scientists performed genetic analyses on samples of their blood and saliva. They found that family members with the condition had lower levels of IGF-1 (insulin-like growth factor 1), a chemical that plays a central role in growth during childhood. Laron patients also had lower blood insulin levels and increased sensitivity to insulin.

In their write-up, the scientists hypothesized that low levels of IGF-1 and insulin could have reduced oxidative damage to DNA. Similar phenomena increase life expectancy in worms, yeast and mice, the scientists said. However, they could not conclude that this was the correct explanation for the observed low rates of cancer and diabetes.

If their hypothesis proves to be correct, it suggests that dietary- or drug-based strategies could be used to tackle the diseases. IGF-1 levels are known to fall in people who fast, or restrict protein intake for several days, for example.

Of course these dietary strategies are fraught with risks, but a drug that reduces the effects of growth-hormone (once a person is fully grown) might hold promise.

As it turns out, Pfizer’s Somavert does just this. The drug is now used to treat acromegaly and gigantism. Longo has approached Pfizer to explore the possibility of sponsoring clinical trials to test this drug for the new applications mentioned above.

Sad Side Note: Although the Laron dwarfs in this study never got cancer or diabetes, they did not outlive their relatives. It turns out that substance abuse and accidents are endemic in that community, and they end-up being an unfortunate equalizer when it comes to life expectancy.

Gene therapy involves replacing or altering a small part of DNA whose abnormal expression causes a disease. The new therapeutic technique has shown promise for the treatment of cystic fibrosis, hemophilia and muscular dystrophy. Now, according to scientists at Weill Cornell Medical Center, perhaps depression should be added to this list as well.

In mice that is. Perhaps someday gene therapy can be used to treat humans as well.

That’s the suggestion made by Michael Kaplitt and colleagues in their write-up summarizing the results of their recent experiments which appears in Science Translational Medicine.

Kaplitt’s team knew that abnormalities in a particular region of the brain-the nucleus accumbens-were associated with depression in humans and behaviors akin to depression in mice (specifically, murine responses to rewards and pleasurable experiences). They knew that the problem in the nucleus accumbens had to do with abnormalities in the way the neurotransmitter serotonin impacted chemical pathways that mediated mood, appetite and sleep patterns. And they knew that most antidepressant drugs acted to regulate serotonin metabolism in the brain.

Kaplitt’s group went from there to isolate the problem with serotonin metabolism in the nucleus accumbens of “depressed” mice. It turned out to be the lack of a single protein, known as p11, which normally serves to transport serotonin receptors to the surface of nerve cells. When p11 was missing or didn’t work properly, nerve cells could produce adequate amounts of serotonin receptors, but the receptors never made it to the surface of the nerve cell membrane where they could bind serotonin and thus trigger normal behavioral responses.

Kaplitt’s team then used somatic gene transfer (that is, “gene therapy”) to replace the gene responsible for producing the defective p11 protein in the nucleus accumbens of their depressed mice. They subsequently observed that the depressive symptoms disappeared.

“We potentially have a novel therapy to target what we now believe is one root cause of human depression,” Kaplitt told BurrillReport. Kaplitt’s team hopes to launch a clinical trial of gene therapy in humans with depression sometime soon.

Drug induced increases in levels of the brain neurotransmitter norepinephrine can overcome memory problems and improve cognitive development in mice with genetically-engineered Down syndrome, according to scientists at Stanford.

Ahmad Salehi and colleagues postulate that similar interventions, if applied early enough in children with Down syndrome, might improve their cognitive development as well.
 
Their write-up appears in Science Translational Medicine.

In the article, Salehi’s group showed that drugs which enhanced norepinephrine signaling in the brains of the genetically engineered mice rapidly restored cognitive function, enabling them to handle simple challenges like building a nest.

The treated mice could make nests as well as normal mice. Untreated mice were unable to do so. The beneficial effects became apparent just hours after treatment was initiated. They waned quickly following discontinuation of the drugs.
 
Salehi’s genetically-engineered mice exhibited early degeneration of the locus ceruleus, a part of the brain that supplies norepinephrine to the hippocampus, which is involved with memory formation. The same findings have been demonstrated in humans with Down syndrome.

Several drugs that have been approved by the FDA for treatment of depression and ADHD have the same effects on brain norepinephrine levels as those used in the Stanford study. Because these drugs have proven to be safe in humans (though not infants), Salehi told BurrillReport he hoped his results would quickly lead to human trials.
 
Previous efforts to modify the course of Down syndrome with drugs have focused on acetylcholine, a separate neurotransmitter that also acts on the hippocampus.