NEJM: Rare fatal genetic disease successfully treated in utero for the first time

Using a protocol developed at UC San Francisco, doctors have for the first time succeeded in treating a fetus with a devastating genetic disorder that is now thriving like a toddler
, a case study in the New England Journal of Medicine reports.

"This treatment expands the scope of fetal treatment in a new direction," said co-senior and corresponding author Tippi MacKenzie, MD, pediatric surgeon at UCSF Benioff Children's Hospital, co-director of the UCSF Center for Maternal-Fetal Precision Medicine, and director of
the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research.
"As new treatments are available to children with genetic disorders, we are developing protocols
to apply them before birth.
"

This childhood disease is one of several lysosomal storage disorders that begin to cause serious damage
to major organs such as the heart before birth.
By initiating enzyme replacement therapy during fetal development, doctors aim to achieve better outcomes than typical postpartum treatment — outcomes that may include early childhood death, extremely low muscle tone, or dependence on a ventilator
.

After six sessions of antenatal enzyme replacement at the Ottawa Hospital, the baby Ella was born
to term.
She is undergoing postnatal enzyme therapy at CHEO, a pediatric hospital and research center in Ottawa, Canada, and is doing well
at 16 months of age.
Her heart and motor function are normal and she is in the developmental stage
.

Ella's father, Zahid Bashir, said: "When we gave birth to Ella, we didn't know if she could walk
.
" "We don't know if she can still talk
.
We don't know if she can still eat
.
We don't know if she'll be able to laugh.

So, as she reaches every milestone, we continue to be amazed
by her progress.
So yes, it's a great thing, and I think sometimes we might take it for granted, but most of the time it's clear to us that she's a miracle
.
”

The triumph of cooperation

The successful treatment is a feat of the UCSF collaboration, and clinical trials of the treatment are ongoing; CHEO and Ottawa Hospital, where patients are diagnosed and treated; Duke University is home to the world's leading experts in Pompe disease
.
" We really need this multidisciplinary team to bring their deep expertise to all aspects of care," said MacKenzie, the Benioff Professor of Child Health and the John G.
Bose Distinguished Professor
of Stem Cell and Tissue Biology at UCSF.
"Enzyme replacement therapy is a new frontier in fetal treatment; I'm excited
to see it grow from a research project in my lab to results that ultimately impact this family.
UCSF is considered the birthplace of fetal surgery, and it is a special privilege
for us to continue expanding existing technologies and treatments to help families facing difficult diagnoses during pregnancy.
”

Typically, families travel to the Fetal Treatment Center at Benioff Children's Hospital at UCSF to participate in clinical trials
.
When Covid restrictions made international travel impossible, experts from two Canadian and two U.
S.
hospitals met with the family via video to discuss alternatives
.
UCSF shared the treatment with the team in Ottawa, where the
family lives.
Throughout the process, the entire team meets weekly via video to discuss the health of the mother and fetus and monitor response to
treatment.

"We have been treating fetal patients with intrauterine therapies for more than 30 years," said
Karen Fung-Kee-Fung, a family maternal-fetal medicine specialist at Ottawa Hospital and professor of obstetrics and gynaecology at the University of Ottawa.
"The emergence of a new treatment that eases the burden of Pompe disease for this family and has the potential to help other families affected by devastating genetic diseases is both exciting and incredibly satisfying
.
" We are very honored and honoured to be part of this international collaboration to help bring about this world's first treatment
.
”

Pranesh Chakraborty, MD, a pediatrician and metabolic geneticist at CHEO and co-leader of the case study, has cared
for the family for years.
Chakraborty said: "This treatment is very promising and I am very happy
for Ayla and her family.
" Chakraborty is also a Fellow at the CHEO Institute and an Associate Professor
at the University of Ottawa.
"I am fortunate enough to be with families who have lost children to these devastating diseases, and I am heartbroken, so this work is very important
to me.
" A big step forward in fetal treatment? Babies born with infantile Pompe disease usually have an enlarged heart and die
within two years if left untreated.
The disease is very rare, affecting less than 1 in 100,000 live births, and is caused
by a mutation in the gene that makes the acid-glucosidase, an enzyme that breaks down glycogen.
With no glycogen or limited glycogen content, glycogen can accumulate
dangerously in the body.

"From our long work treating patients with Pompe disease at Duke, we know firsthand the critical importance of starting treatment early," said Jennifer Cohen
, MD, co-first author of the study and assistant professor in the Department of Pediatric Medical Genetics at Duke University School of Medicine.
”

Duke has played a key role in many advances in the field of Pompe disease, including developing alglucosidase alfa as the first Food and Drug Administration-approved enzyme replacement therapy (ERT) for Pompe disease, determining the role of high and sustained antibody titers for ERT, tracking treatment response using biomarkers, and establishing an immune tolerance induction protocol for the most severe patients, Priya Kishnani, Ph.
D.
, noted, "All of these advances are critical to the treatment and response of this particular patient.
" Intrauterine treatment is a new frontier
for patients with Pompe disease.
”

Pompe is one of eight lysosomal storage diseases, and UCSF has received FDA approval for treatment
with intrauterine enzyme replacement therapy in a Phase 1 clinical trial in 10 patients.
Other diseases are mucopolysaccharidosis types 1, 2, 4a, 6 and 7, Gaucher disease types 2 and 3, and Wolmann's disease
.

The researchers hope that the success of this first application and the publication of this case study will raise the profile of UCSF clinical trials to parents and doctors who treat these diseases that are known to be at risk of transmitting them
.

"It's important to see how well Ayla is doing and conducting clinical trials to determine if this fetal therapy will be a good option for other families whose newborns are not being treated early enough," said Chakraborty, who leads Ontario's provincial program for newborn screening, which is based at CHEO
.
"We are working to improve the chances of
other Canadian families receiving this trial.
"?

Two other patients with different lysosomal diseases have now joined UCSF's clinical trials, and both have completed courses of prenatal enzyme replacement therapy
.
The first patient delivered in late October 2022 and the second patient will deliver
in early November 2022.
Both are
well done.

"It's exciting to continue this research, which is an important step in the evolution of fetal treatment, from surgical procedures for anatomical conditions to medical treatments
for genetic conditions," MacKenzie said.

Original:

Marisa Schwab, MD, and Billie Lianoglou, MS, in the UCSF Department of Surgery and Anita Moon-Grady, MD, and Paul Harmatz, MD, in the UCSF Department of Pediatrics, also contributed to this research.
Please refer to the paper for additional co-authors.