Researchers from Boston University and Boston Medical Center have recently uncovered that base editing is able to correct the gene mutation which causes alpha-1 antitrypsin deficiency (A1AD).
This condition impacts both the lungs and the liver. It is most frequently caused by a Z mutation within the SERPINA1 gene. This is a single base substitution which leads to the misfolding of the AAT protein which then builds up within the hepatocytes, leading to damage.
Currently, A1AD is created with augmentation therapy which can slow progression of lung disease. However, there have yet to be any treatments for the effects this disease has on the liver.
This finding was the result of a study recently published in Molecular Therapy. The hope is that this study will pave the way for human trials.
Base editing is not the same as the frequently discussed CRISPR technology. This is because the base editors do not break the DNA. This helps ensures that the double-strand doesn’t break, that the editing doesn’t occur to something that is not the target, and that unwanted mutations do not occur.
In this investigation, liver cells from patients (iHeps) which mimicked liver hepatocytes were used. These cells are the largest producer of alpha-1 antitrypsin. Base editing was then used to correct the Z mutation.
As a result, the effects of the disease within the cells were reduced, allowing researchers to confirm the base editing (utilizing adenine base editors) was successful within the human cells. The same result was found using stem cells.
The edited cells had reduced ATT accumulation and increased secretion. ER stress was decreased in the cells as well. Further, there were no off-target mutations.
That said, they expect Alpha-1 antitrypsin deficiency to be one of the first conditions to advance to human trials.
You can read more about this treatment and its potential in Alpha-1 antitrypsin deficiency here.