PHILADELPHIA, May 5, 2021 /PRNewswire/ -- When Luke Terrio
was about seven months old, his mother began to realize something
was off. He had constant ear infections, developed red spots on his
face, and was tired all the time. His development stagnated, and
the antibiotics given to treat his frequent infections stopped
working. His primary care doctor at Children's Hospital of
Philadelphia (CHOP) ordered a
series of blood tests and quickly realized something was wrong:
Luke had no antibodies.
At first, the CHOP specialists treating Luke thought he might
have X-linked agammaglobulinemia (XLA), a rare immunodeficiency
syndrome seen in children. However, as the CHOP research team
continued investigating Luke's case, they realized Luke's condition
was unlike any disease described before.
Using whole exome sequencing to scan Luke's DNA, CHOP
researchers discovered the genetic mutation responsible for his
condition, which prevents Luke and patients like him from making B
cells and antibodies to fight infections. The study describing
Luke's condition, which CHOP researchers named PU.1 Mutated
agammaglobulinemia (PU.MA), was published today in the Journal
of Experimental Medicine.
"It can be pretty scary for a family whose child has a
mysterious illness" said Neil D.
Romberg, MD, an attending physician with the Division of
Allergy and Immunology at CHOP and senior author of the paper. "In
this case, science provided an explanation, thanks to numerous
departments at CHOP, including the Roberts Individualized Medical
Genetics Center, the Center for Spatial and Functional Genomics,
and the Cancer Center. Understanding the cause of Luke's condition
absolutely helped us know what direction to take his therapy."
"I was so impressed with how all of the specialists at CHOP
worked together as a team, even though they specialized in
different areas," said Luke's mother, Michelle. "They knew
something was wrong with Luke, and they didn't stop digging until
they figured it out."
Figuring Out the "Why"
To pinpoint the gene at fault, CHOP researchers compared whole
exome sequences from 30 patients across the globe who were born
without B lymphocytes, the cells which produce antibodies. From the
larger group, they identified six patients, including Luke, who had
a mutation in a gene called SPI1, which encodes the PU.1
protein. PU.1 helps B lymphocytes developing in bone marrow to open
up "doors" in their chromatin, a type of tightly packed DNA.
Without PU.1, those door remains shut, and the B cells never form.
The six PU.MA patients, who ranged in age from 15 months to 37
years, each had different SPI1 mutations but shared
insufficient levels of PU.1, absent B cells and, consequently, zero
antibodies.
To validate the roles of SPI1 and PU.1, the researchers
used CRISPR to reconstitute the condition in vitro. Using donated
cord blood of patients who lacked SPI1 mutations, the
researchers employed CRISPR to edit the patients' SPI1
mutations into the donated cord blood genes. After culturing the
cells for six weeks and sequencing the cells that survived, they
found B cells were specifically intolerant of PU.1 changes.
Treatment Without a Playbook
Because Luke's condition was entirely new, there was no playbook
for his family or his medical team to follow. After consulting with
the research team, the family decided to proceed with a bone marrow
transplant in the hope that the procedure would help him make his
own B cells and antibodies. Soon they discovered they had a perfect
match living under their own roof: Luke's older brother, Jack.
At three and a half years of age, Jack, who has high-functioning
autism, donated his bone marrow to Luke. The transplant was
successful at getting Luke to produce his own B cells. Until those
B cells are able to create enough protective antibodies by
themselves, Luke continues to receive infection protection from the
antibody infusions he receives every two weeks.
"We call them his ninjas," said Michelle describing antibodies.
"We tell him that he doesn't make his own ninjas, so he needs these
ninja infusions to fight the germs and keep him safe."
Thanks to those "ninjas" and his brother's gift of bone marrow,
Luke is now an energetic 4-year-old boy who loves Transformers,
fire trucks, and his balance bike. Before his bone marrow
transplant and the infusions, he needed naproxen twice a day for
his joint pain, required leg braces to straighten his legs, and
would lie on the floor exhausted tire after 10 minutes of activity.
Now, he always seems to be running, often with his dog Charlie
chasing behind him.
"Knowing the source of the problem removed the boogeyman for the
Terrios and allowed them to move their lives forward," Romberg
said. "Figuring out Luke's case not only helped guide his therapy
and gave answers to others suffering with this rare condition – in
some cases for years – but also opens the door to learning more
about the effects of PU.1 on a variety of more common human
diseases and conditions."
Le Coz et al. "Constrained chromatin accessibility in
PU.1-mutated agammaglobulinemia patients," Journal of
Experimental Medicine, online May 5,
2021, DOI: 10.1084/jem.20201750
About Children's Hospital of Philadelphia: Children's Hospital of
Philadelphia was founded in 1855
as the nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals, and pioneering
major research initiatives, Children's Hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. In addition,
its unique family-centered care and public service programs have
brought the 595-bed hospital recognition as a leading advocate for
children and adolescents. For more information, visit
http://www.chop.edu
Contact: Camillia Travia
Children's Hospital of Philadelphia
(425) 492-5007
traviac@chop.edu
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SOURCE Children's Hospital of Philadelphia