Summary: Both the ApoE genotype and the sex of the mouse impacted the manner in which the animals with spinal cord injury responded to hypoxia treatment. Females with the ApoE e4 gene had a negative response to intermittent hypoxia.
Source: University of Kentucky
Spinal cord injuries (SCIs) are not only life-threatening at the time of the event, but they can also lead to secondary complications and loss of function in sensory and motor systems.
Researchers at the University of Kentucky recently published a unique study focusing on SCIs in eNeuro. It is unique because it is the first to look at how genotype and sex differences in the human population may impact the response to treatment strategies for SCIs, for which there are currently no FDA-approved therapeutics.
Although many studies have previously examined treatment strategies that are effective at restoring function after experimental SCI, there is currently a lack of successful translation of these strategies from animal models to the SCI population. This led to the group’s hypothesis that there may be factors in the human population, such as sex and genetic background which alter individuals’ ability to respond positively to treatments.
Lydia Strattan, a graduate student in the UK Department of Neuroscience, says to address this they utilized spinally injured male and female mice that express the human APOE gene.
“There are three versions of this gene and one version, known as e4, is infamous for being closely associated with the development of Alzheimer’s Disease and negative outcomes after traumatic brain injury. However, APOE’s impact on recovery after SCI has remained understudied. Therefore, we examined how the different variants of APOE influence the response to a promising therapeutic strategy known as intermittent hypoxia, which is currently in clinical trials for improving respiratory function after SCI. We found that both APOE genotype and sex impacted the manner in which spinally injured mice respond to intermittent hypoxia treatment.”
Ultimately the study found that females who express the e4 allele of APOE have a negative response to intermittent hypoxia, indicating that treatment strategies may not be equally effective or beneficial for all individuals. This phenomenon could contribute to the historical difficulty of translating SCI therapeutics from the bench to the bedside.
When therapeutics are being tested pre-clinically, they are typically evaluated for efficacy in a very homogenous animal population. For example, rodent studies of SCI are often conducted in either males or females – not both – with similar genetic backgrounds. Since the data from this new study shows that both sex and APOE genotype can influence how individuals respond to treatment strategies, they hope it emphasizes the importance of considering the diversity of the human population when developing treatments pre-clinically.
“Our results could help pave the way for personalized medicine in SCI and enhance the translational potential of treatments that improve functional recovery and, consequently, quality of life for injured individuals,” Stratton says.
In addition to Strattan, several other researchers from the University of Kentucky contributed to the study including Daimen Britsch, Chris Calulot, Rachel Maggard, Erin Abner, Lance Johnson, and Warren Alilain. Their collaboration represented several groups including the Spinal Cord and Brain Injury Research Center, Sanders-Brown Center on Aging, Department of Neuroscience, Department of Biostatistics, Department of Epidemiology and the Department of Physiology.
The team believes the big takeaway from their work is that SCIs are highly variable injuries and the people who are living with SCIs are each unique individuals. Due to this they believe it is important to not only consider the type of injury, but also the sex and genetic background of the individuals when testing treatment strategies pre-clinically.
About this spinal cord injury research news
Source: University of Kentucky Contact: Press Office – University of Kentucky Image: The image is credited to University of Kentucky
Spinal cord injuries can abolish both motor and sensory function throughout the body. Spontaneous recovery after injury is limited and can vary substantially between individuals. Despite an abundance of therapeutic approaches that have shown promise in preclinical models, there is currently a lack of effective treatment strategies that have been translated to restore function after SCI in the human population.
We hypothesized that sex and genetic background of injured individuals could impact how they respond to treatment strategies, presenting a barrier to translating therapies that are not tailored to the individual. One gene of particular interest is APOE, which has been extensively studied in the brain due to its allele-specific influences on synaptic plasticity, metabolism, inflammation, and neurodegeneration.
Despite its prominence as a therapeutic target in brain injury and disease, little is known about how it influences neural plasticity and repair processes in the spinal cord. Utilizing humanized mice, we examined how the ε3 and ε4 alleles of APOE influence the efficacy of therapeutic intermittent hypoxia (IH) in inducing spinally-mediated plasticity after cervical SCI. IH is sufficient to enhance plasticity and restore motor function after experimental SCI in genetically similar rodent populations, but its effect in human subjects is more variable (Golder, 2005; Hayes et al., 2014).
Our results demonstrate that both sex and APOE genotype determine the extent of respiratory motor plasticity that is elicited by IH, highlighting the importance of considering these clinically relevant variables when translating therapeutic approaches for the SCI community.
There is currently a critical need for therapeutics that restore motor and sensory function effectively after cervical spinal cord injury. Although many therapeutic approaches, including intermittent hypoxia, are being investigated for their potential to enhance spinal plasticity and improve motor outcomes after SCI, it is unknown whether the efficacy of these treatment strategies is influenced by individuals’ genetic background.
Here we show that APOE genotype and sex both play a role in determining the propensity for motor plasticity in humanized mice after cervical SCI.
These results indicate that sex and genetic background dictate how individuals respond to therapeutic approaches, thereby emphasizing the importance of developing personalized medicine for the diverse SCI population.