Using gene transfer techniques pioneered by
University of Florida faculty, Taiwanese doctors have restored some movement in
four children bedridden with a rare, life-threatening neurological disease.
The first-in-humans
achievement may also be helpful for more common diseases such
as Parkinson's that involve nerve cell damage caused
by lack of a crucial molecule in brain tissue. The
results are reported today (May 16) in the journal Science
Translational Medicine.
The children in the study,
who ranged in age from 4 to 6, inherited a rare disease known as aromatic
L-amino acid decarboxylase deficiency, or AADC. Patients with AADC are born
without an enzyme that enables the brain to produce the neurotransmitter
dopamine. They generally die in early childhood.
In a phase 1 clinical trial
led by Paul Wuh-Liang Hwu, M.D., of the National Taiwan University Hospital,
surgeons used a delivery vehicle called an adeno-associated virus type 2 vector
to transport the AADC gene into localized areas of the brains of three girls
and a boy.
Before therapy, the
children showed practically no spontaneous movement and their upper eyelids
continually drooped. After receiving the corrective gene, the children
gradually gained some head movement. Sixteen months afterward, the children's
weight had increased, one patient was able to stand and the other three were
able to sit up without support.
The study shows gene
therapy that targets AADC deficiency is well-tolerated and leads to improved
motor development and function, according to co-authors Barry Byrne, M.D.,
Ph.D., director of UF's Powell Gene Therapy Center, and Richard O. Snyder,
Ph.D., director of UF's Center of Excellence for Regenerative Health Biotechnology.
Both are members of the UF Genetics Institute.
"The children in
this study have the most severe form of inherited movement disorder known, and
the only treatments so far have been supportive ones," said Byrne, a
pediatric cardiologist and associate chairman of the department of pediatrics
in the College of Medicine. "It is gratifying to see it is possible to do
something to help them, other than providing feeding tubes and keeping them
safe. This absolutely opens the door to the possibility of even earlier
treatment of neurological diseases by direct gene transfer, and has
implications for Parkinson's disease, ALS and even cognitive diseases such as
dementia when caused by gene defects."
The Powell Gene Therapy
Center provided expertise to the Taiwanese physicians on treating the patients
and engineering the corrective gene that spurs production of the absent AADC
enzyme. UF's Center of Excellence for Regenerative Health Biotechnology
manufactured the vector, packaging genetic material it received from Taiwan
into virus particles that were purified, characterized and tested for sterility
and stability before being shipped to the clinic for use in patients.
"We are ecstatic
that we manufactured a product that provided therapeutic benefit to these
patients," said Snyder, an associate professor in UF's department of
molecular genetics and microbiology. "What really makes it special is
there are just a handful of examples of gene therapy in children in the world,
and these patients all improved."
Doctors injected the AADC
vector into a brain area called the putamen, a site known for AADC activity and
part of a "loop" of brain connections related to movement.
Postoperative CT and MRI
scans of the patients showed no evidence of bleeding and all four patients were
discharged within a week. Three to six months after gene transfer, all the
children had gained weight, including one patient who doubled her weight within
a year.
Before gene therapy, all
patients showed low raw scores in cognition and motor development on a scale
called the Comprehensive Developmental Inventory for Infants and Toddlers.
Afterward, scores in both areas increased. Parents reported the children also
slept better and had improved eye coordination, emotional stability and body
temperature stability.
Eight additional children
— four in Taiwan and four in the United States — are expected to receive the
experimental treatment, Byrne said.
Journal reference: Science
Translational Medicine
Provided by University
of Florida
No comments:
Post a Comment