A new gene therapy has the ability to fix a defective sense of smell in mice by repairing problems with the cilia on their olfactory neurons. This study suggests that abnormalities in cilia can be treated, but it remains unclear how these findings can be applied to other organs.
The researchers published their findings in the journal Nature Medicine. Cilia can be found on the surface of many cells, and they affect functions like sensory perception, movement and cell signaling. Damaged cilia can be the result of genetic mutations, and can cause kidney and liver cysts, extra digits, obesity, blindness and hearing loss.
These mutations and their cellular mechanisms have been well studied, but there haven’t been many therapies to restore their function. Jeffrey Martens, a pharmacologist at the University of Michigan in Ann Arbor, lead author, and his colleagues used mice that had a mutant protein causing similar effects to polycystic kidney disease in humans. These mutations are called intraflagellar transport 88 (IFT88) and they disrupt cilia expression and function. The mice are called Oak Ridge polycystic kidney (ORPK) mice and die by early adulthood.
ORPK mice had fewer cilia than their healthy counterparts, and their cilia remained shortened and malformed. To reverse this defect, a functional IFT88 protein was inserted into an adenovirus and injected into the noses of the ORPK mice. The injection resulted in restored cilia and a normal sense of smell. The authors were unable to conduct behavioral tests in adult mice, since most die young, but treated mice were better at suckling and feeding that resulted in a 60% increase in body weight.
How this will translate to other organs is yet unclear. The possible side effects include the viral vector spreading to unintended cells as well as immune responses. Martens hopes that this could be potentially used to correct blindness or kidney dysfunction.
Reference: “Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model” by Jeremy C McIntyre, Erica E Davis, Ariell Joiner, Corey L Williams, I-Chun Tsai, Paul M Jenkins, Dyke P McEwen, Lian Zhang, John Escobado, Sophie Thomas, Katarzyna Szymanska, Colin A Johnson, Philip L Beales, Eric D Green, James C Mullikin, NISC Comparative Sequencing Program, Aniko Sabo, Donna M Muzny, Richard A Gibbs, Tania Attié-Bitach, Bradley K Yoder, Randall R Reed, Nicholas Katsanis and Jeffrey R Martens, 2 September 2012, Nature Medicine.
DOI: 10.1038/nm.2860
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