NEJM: The world's first successful treatment of a rare genetic disease in an unborn baby in utero

Pompe's disease, or glycogen accumulation disease type II, is a rare and fatal autosomal recessive genetic disease, which is due to gene mutations encoding acidic α-glucosidase (GAA), resulting in lack or significant reduction of GAA enzyme activity in lysosomes, glycogen can not be degraded and stored in the lysosomes of cells such as skeletal muscle, cardiac muscle and smooth muscle, resulting in lysosomal swelling, cell destruction and organ function damage, and causing a series of clinical manifestations
.

Newborn screening can detect the disease in time and initiate enzyme replacement therapy (ERT) with recombinant α-glucosidase soon after birth, which can improve patient outcomes, but in severely ill babies, irreversible organ damage
has begun as it develops in the womb.

Doctors and researchers at the University of California, San Francisco, Duke University and the University of Ottawa have successfully used enzyme replacement therapy (ERT) for the first time to treat a fetus with Pompe disease still in the womb, and the little girl is now one and a half years old, has reached developmental milestones, has a normal heart and muscle function, can walk, and has normal biomarkers of muscle damage and glycogen accumulation
.

The study, titled In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease, was published in the New England Journal of Medicine (NEJM).

The little girl who received treatment, Ayla Bashir, is now one and a half years old and is growing
up healthy after treatment.
She developed a rare genetic disease, Pompe disease
.

Worldwide, the incidence of Pompe disease is less than 1 in 138,000, but in some regions, the incidence may be higher, for example, the incidence of Pompe disease in Taiwan, China, is 1
in 50,000.

Pompe disease usually begins before birth and, if left untreated, usually dies before the age of 2 years
.
Treatment usually begins after birth, but postnatal treatment cannot repair irreversible organ damage
that has occurred in the womb.
Ella's parents were close relatives who each carried a copy of the GAA gene heterozygous mutation, and they had two children, both of whom died shortly after birth from Pompeie disease
.

While some people may develop Pompe disease later in life, or suffer from less severe Pompe disease, Ella was diagnosed with the most severe form of Pompe disease, a homozygous mutation in the GAA gene that prevented her cells from producing the GAA enzyme and was treated after birth, too late for her
.

Previous experiments in mice have shown that enzyme replacement therapy in the womb before birth can control the development of
Pompe disease.
So Jennifer Cohen et al.
, a pediatric geneticist at Duke University School of Medicine, began an early-stage clinical trial covering several lysosomal storage disorders (LSDs),
including Pompe disease.

When Ella's mother was 24 weeks pregnant, the team began injecting GAA enzyme through the umbilical vein
.
Her mother had six injections, once
every two weeks.
After birth, the medical team will give Ella weekly injections that last a lifetime
.

Jennifer Cohen says this enzyme replacement therapy in utero is safe
for both mother and child.
But until more patients are treated and monitored in clinical trials, it is not yet possible to determine whether this prenatal enzyme replacement therapy is always a safe and effective option
.
So far, the research team has also administered this treatment to two other babies with lysosomal storage disorder (LSD), but the timing is still early and the results of the treatment are unclear
.

This prenatal enzyme replacement therapy may also be used to treat other rare diseases
in the future.
But it is important to prove that before trying any new treatment in utero, it is first proven safe, and before undergoing treatment in utero, it is confirmed that it is effective
after birth.

It's unclear what the long-term will be for Ella and other children who have received this treatment, but Jennifer Cohen said she is "cautiously optimistic" and wants to be cautious and monitored throughout the patient's life, where the patient's performance in the first five years is critical
.