Gene Transfer Method of EPO Improves Cognition in Mouse Study

Administration of the hormone erythropoietin (EPO) using a gene transfer method improved spatial cognition, stimulated the branching of nerve stem cells, and preserved the brain region known as the hippocampus in a mouse model of Huntington’s disease, a study reports. 

These findings suggest this treatment strategy may reduce cognitive impairment in people with Huntington’s disease. 

The study, “Lentiviral delivery of human erythropoietin attenuates hippocampal atrophy and improves cognition in the R6/2 mouse model of Huntington’s disease,” was published in the journal Neurobiology of Disease.

EPO is a protein hormone produced mainly in the kidneys that stimulates the production of red blood cells. In the central nervous system (CNS), which is composed of the brain and spinal cord, EPO is involved in maintaining nerve cell (neuron) survival and cell growth. 

The application of EPO has been shown to improve learning and memory in mouse models for stroke and traumatic brain injury, and also found to slow disease progression in models of amyotrophic lateral sclerosis. In humans, EPO improved cognitive function in disorders such as schizophrenia and multiple sclerosis.  

However, administering the large amounts and multiple doses of EPO needed to achieve therapeutic effects can result in side effects such as blood clots and stroke. 

To overcome these limitations, long-term administration of EPO in the CNS can be achieved using a gene transfer system such as harmless, slow-growing lentiviral vectors, which can target most cell types in the CNS. 

In the study, researchers based at the Charité – Universitätsmedizin Berlin, in Germany, evaluated the effect of using a lentiviral vector carrying the gene for human EPO (LV-hEPO) in a mouse model of Huntington’s disease. 

This mouse model carries the mutant form of the HTT gene and mimics many of the features of Huntington’s disease. 

The team injected LV-hEPO into the brains of 8-week-old female mice. Control mice were either untreated or injected with a lentivirus encoding a marker protein. 

After 30 days, hEPO production was detected in the areas of the brain affected by Huntington’s such as the cortex, striatum, and hippocampus, but not in the brains of control mice. Levels of red blood cells were unaffected in treated mice. 

Progressive weight loss is a prominent feature of this Huntington’s mouse model and a useful measure of disease progression. However, all three groups of mice (treated and controls) progressively lost weight, while their healthy littermates gained weight over 30 days, “suggesting that hEPO does not prevent weight loss in this model,” the researchers wrote. 

In the mouse model of Huntington’s, the animals displayed motor abnormalities, such as twitching, resting tremors, or stress-induced seizures. Again, LV-hEPO treatment did not reduce the progressive deterioration of motor performance compared to the control mice.

In contrast, maze-based tests for spatial working memory found that LV-hEPO-treated mice showed increased spatial scores compared to control mice at both 15 and 30 days post-injection. They also demonstrated spatial cognition similar to the levels of healthy mice. 

Of note, spatial working memory allows for the recording of information about one’s environment and spatial orientation, while spatial cognition refers to the acquisition and use of knowledge about spatial environments.

To determine if these spatial improvements reflected disease modification, MRI scans were used to monitor different areas of the brain for atrophy — the thinning of tissue caused by the degeneration of cells. 

The volume of tissue in the cortex, striatum, and hippocampus decreased progressively in control mice. In contrast, atrophy in the hippocampus was significantly reduced in LV-hEPO-treated mice, suggesting the “specific preservation of hippocampal tissue.” No differences in atrophy of the other regions were observed. 

The authors speculated that “the hippocampal preservation observed in the LV-hEPO-treated mice may have permitted the maintenance of spatial cognition in these animals.”

A hallmark of Huntington’s disease is the buildup of mutant huntingtin protein aggregates. These were found in the brains of Huntington’s mice and were not lowered by LV-hEPO treatment.

Finally, while treatment did not improve the growth of new neurons in the hippocampus of these mice, it did increase the outgrowth of projections from the cell body of neurons called neurites, which the researchers suggest could be “a mechanism by which EPO may protect against hippocampal volume loss.”

Furthermore, LV-hEPO-treatment significantly increased the branching of neuroblasts — a precursor nerve cell equivalent to stem cells. 

“In summary, we present a treatment regime for CNS-restricted EPO expression in [Huntington’s disease] transgenic mice, which has beneficial effects on [Huntington’s disease]-related phenotypes while surpassing adverse consequences from long-term systemic applications of EPO,” the researchers wrote. 

“These results may inform future treatment strategies for [Huntington’s disease] patients and other neurodegenerative diseases.”