GENE CORRECTED STEM CELL THERAPY TO TREAT CYSTIC FIBROSIS
DEVELOPED AT STANFORD UNIVERSITY
A team of researchers at Stanford University has used the gene editing
tool commonly known as CRISPR to repair the gene that causes cystic
fibrosis in airway stem cells, which they say is a critical step to
develop a gene therapy for the disorder.
The
researchers showed that the repaired airway stem cells could give rise
to other airway cells and could produce functional cystic fibrosis
transmembrane conductance regulator protein, which is faulty in cystic
fibrosis patients. The study represents a proof of concept for the
repair of genes that cause airway disorders. A study describing these
results was published online in Cell Stem Cell on December 12,
2019. Postdoctoral scholar Sriram Vaidyanathan, PhD is the first co-lead
author and Matthew Porteus, MD, PhD, professor of pediatrics is the
lead co-senior author. Other co-lead authors include Ameen Salahudeen,
MD, PhD, Zachary Sellers, MD, PhD, Dawn Bravo PhD. Other co-senior
authors include Tushar Desai, MD, Jayakar Nayak, MD, PhD and Calvin Kuo
MD,PhD.
A devastating childhood disease: Cystic
fibrosis affects about 75,000-100,000 people globally. CF patients
suffer from chronic lung infections that eventually cause lung failure
and death. In addition, patients may also suffer from problems in
several other organs. CF patients have an average life expectancy of
about 40 years. CF is a fatal disease caused by mutations in a single
gene (the cystic fibrosis transmembrane conductance regulator (CFTR)).
The CFTR gene encodes an ion channel that transports chloride in cells
that express the gene. In CF patients, the channel is non-functional and
chloride transport is blocked. This results in a build-up of thick
mucus in the airways and also results in damage to other organs such as
the pancreas.
The quest for a cure: Gene
therapy has been attempted to treat several genetic diseases such as
sickle cell disease and thalassemia over the past two decades with some
individual successes. The discovery of CRISPR enabled the precise
manipulation of genes and made it feasible to develop gene therapies for
many more diseases. CRISPR was most readily applied to develop cures
for blood disorders such as sickle cell disease because of our increased
familiarity with blood stem cells and our ability to readily culture
and transplant them into patients. Indeed, the first clinical trials to
test the use of CRISPR to treat sickle cell disease, a blood disorder,
have already started even though the technology is relatively new.
Although
CF was one of the first diseases for which gene therapy was attempted,
attempts have been unsuccessful so far. The development of CRISPR
renewed hopes for a gene therapy for CF. The application of CRISPR to
treat lung disorders such as CF was challenging because methods to apply
CRISPR to effectively edit airway stem cells had not been developed.
The team consisting of Dr. Vaidyanathan, Dr. Porteus and colleagues have
developed a method to correct one CF causing mutation (DF508)
which affects over 70% of patients in the US and Europe. This
publication describes the correction of a commonly observed CF causing
mutation with efficiencies over >40% in airway stem cells. This is
over a 100-fold improvement over previous work correcting the same
mutations in other cell types and makes it possible to correct CF
causing mutations in a clinically applicable manner. Further work is
necessary to perfect the transplantation of edited airway stem cells in
the airways to develop a durable treatment for CF.
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