Inhaled CF gene therapy shows lasting promise with single dose in primates
Treatment designed for all patients, regardless of disease-causing mutation
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A single dose of an inhaled experimental gene therapy for cystic fibrosis (CF) — one designed to treat people regardless of their disease-causing genetic mutation — was shown in an animal model to sustainably boost CFTR gene activity and protein levels in the lungs and spread to several other organs.
In the preclinical study, those benefits, seen in nonhuman primates, were sustained for six months. Further, the viral delivery vector did not trigger a significant immune response, supporting longer dosing intervals, or periods between doses — which, the researchers say, would “represent an important clinical advantage.”
According to the team, “these findings support the feasibility of achieving durable pulmonary gene transfer following a single administration of [a viral]-based CFTR vector and provide information relevant to the development of longer dosing intervals for CF gene therapy.”
The study, “Durational Study of Persistent Transduction of Rhesus Macaque Lung and Other Organs Following Single Dosing with AAV1-CFTR,” was published in the journal Human Gene Therapy.
CF is an inherited disorder caused by mutations in the CFTR gene, which encodes a protein of the same name that helps move salt and water across cell membranes. When CFTR doesn’t work properly, thick mucus builds up in the lungs, pancreas, intestines, and other organs.
Approved CFTR modulator therapies have improved the health of many people with CF. However, such treatments work only for patients with certain mutations. And, despite years of research, an effective gene therapy to replace the defective CFTR gene and help all people with CF has yet to reach the clinic.
Gene therapy designed to require less-frequent dosing
One novel approach is to deliver a modified version of CFTR to cells that doesn’t function to move salt and water across cell membranes. Instead, such a version would restore a patient’s own faulty CFTR protein by boosting folding and function. This process is known as transcomplementation.
A successful gene therapy for CF using this approach would require repeated dosing throughout life. Because neutralizing antibodies can develop against the viral vectors used to deliver a gene therapy — potentially reducing its effectiveness — longer dosing intervals would represent a key clinical advantage.
Scientists at Johns Hopkins University in Maryland designed such a therapy, dubbed AAV1-delivered delta27-264 CFTR, and have now tested it in four juvenile rhesus macaques. Each received a single dose sprayed into the airway, with two untreated animals serving as controls.
Tissue analysis conducted about six months later detected the genetic material from the therapy throughout the airways and lungs of all treated animals. It was also found in various tissues outside the lungs — specifically, the liver, pancreas, intestine, spleen, lymph node, heart, and kidneys — with the highest levels in the liver and the lowest in the heart.
Additionally, the researchers noted, vector levels in animals given a steroid around the time of dosing were roughly 30 times higher than those observed in an earlier study without the steroid.
CFTR messenger RNA, the molecule that carries the genetic code to serve as a template for protein production, was elevated in treated versus untreated animals across all tissues. This included the respiratory tract, digestive tract, and lymphoid tissue, as well as the heart and kidney. Likewise, CFTR protein levels were also increased in treated animals in the airways, lung tissue, and liver.
Single dose produced sustained gene activity
The team then examined two cell types considered important targets for CF gene therapy: basal cells, which are progenitor cells that replenish the airway lining, and ionocytes, specialized airway cells that express high levels of CFTR and help regulate airway surface fluid.
Experiments detected significantly higher levels of CFTR overlapping with markers of both basal cells and ionocytes in treated animals compared with untreated animals.
By the end of the study, all treated animals had developed neutralizing antibodies against the AAV vector, the researchers noted. Still, immune response to AAV’s outer shell remained low, with one animal showing a positive response at least three times higher than controls. The remaining treated animals showed responses at or lower than the threshold, per study data.
Overall, the levels of proinflammatory signaling proteins and molecules remained similar between treated and untreated animals, suggesting no pattern of inflammation across the body. All animals gained weight over the course of the study, and blood test results showed no abnormalities linked to the treatment.
The researchers concluded that a single-airway dose of this gene therapy produced sustained gene activity and protein expression in the lungs, along with detectable effects in other organs. Further, according to the team, the treatment’s use caused only limited immune activation over six months.
The results indicate that the “durability of expression supports the potential feasibility of extended dosing intervals and informs the development of repeatable AAV-based gene therapies for CF,” they wrote.
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