Kenneth Kaufman, PhD's head shot. PrincipaI Investigator: Kenneth Kaufman, PhD
Key Personnel: Bruce Trapnell, MD, MSRobert Wood, PhD, MD

Hereditary pulmonary alveolar proteinosis (PAP) is a rare genetic disease in which the ability of oxygen to pass into the lungs is poor because proteins block the path to the blood stream. The current treatment is to physically wash the lungs every few months. A Cincinnati Children’s patient with PAP was examined and found to have a change in a gene called the GM­CSFα receptor gene. Changes in this gene have been found in other patients with PAP. However, the patient's brother has the same DNA change and did not develop PAP. We sequenced the whole exome (an exome is composed of the parts of the DNA from the genome that provide the code for proteins) of the patient, brother and parents to identify additional DNA changes that caused the patient to develop PAP and spared her brother from the disease. We found a rare DNA change in one of the affected child’s genes, but did not find the DNA change in her brother. The DNA change is predicted to prevent the protein from doing its job. The gene of interest codes for a protein that is important in lung biology.

In this study, we will use genome editing technology to introduce the gene and GM-CSFα receptor changes found in the patient with PAP, to make a mouse model. If these mice develop PAP then we know that the DNA changes we found are important in causing PAP. We will also make mice that have only changes in the gene of interest OR the GM-CSFα receptor. These mice will allow us to determine if both DNA changes are necessary to cause disease or if only one of them is enough. We will also transplant normal lung macrophages (an important cell that keeps the lungs clean) into the mice to see if we can cure the disease.