In-utero ERT With Lumizyme Effective in Child With Pompe
The successful outcome is the first in-utero use of the therapy with the disease
A 1-year-old toddler with infantile-onset Pompe disease has normal heart and motor function and is growing well after receiving in-utero enzyme replacement therapy (ERT) with Lumizyme (alglucosidase alfa) and standard postnatal immunotherapy, according to a report.
The successful outcome with Ayla is the result of the first in-utero use of ERT in Pompe disease. It was a product of a collaboration between the University of California, San Francisco (UCSF), where the clinical trial IUERT (NCT04532047) on the treatment is being conducted, the Children’s Hospital of Eastern Ontario (CHEO), The Ottawa Hospital, where she was diagnosed and treated, and Duke University.
“When we were having Ayla, we didn’t know if she’d be able to walk,” said Zahid Bashir, Ayla’s father. “We didn’t know if she’d be able to talk. We didn’t know if she’d be able to eat. We didn’t know if she’d be able to laugh. So, as she hits each of these milestones, we continue to be amazed at her progress. So, yeah, it’s quite something, that I think sometimes we may take for granted, but most of the time we’re quite aware that she’s a miracle.”
IUERT — In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases — is a Phase 1 trial that’s evaluating maternal and fetal safety, and feasibility, of in-utero ERT for eight lysosomal storage diseases, including Pompe. The study is still recruiting and seeks to enroll about 10 patients.
“This treatment expands the repertoire of fetal therapies in a new direction,” said Tippi MacKenzie, MD, principal investigator of the trial, in a university press release. “As new treatments become available for children with genetic conditions, we are developing protocols to apply them before birth.”
The report, “In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe’s Disease,” was published in the New England Journal of Medicine.
A feature of Pompe is the abnormal cellular buildup of glycogen, a sugar molecule, in different organs and tissues such as the heart and other kinds of muscle. Lysosomal storage diseases are marked by the lack of certain enzymes inside lysosomes that break down complex, larger molecules.
The condition is caused by a missing or nonworking protein called acid alpha-glucosidase (GAA), an enzyme responsible for breaking down glycogen. ERT is a standard therapeutic approach for Pompe and involves delivering a working version of the GAA enzyme.
Children with infantile-onset Pompe disease have very low GAA enzyme activity (typically less than 1% of normal). As a result, their symptoms usually start within a few months of birth, but heart disease is already observed during pregnancy. Early treatment with ERT after birth doesn’t completely prevent organ damage.
A baby girl named Ayla
A team of researchers describe the case of a baby girl named Ayla with cross-reactive immunologic material (CRIM)-negative infantile onset Pompe disease whose mother is enrolled in the IUERT trial. CRIM-negative patients don’t produce any GAA protein and are more likely to develop anti-ERT antibodies, which limit a treatment’s effectiveness.
Ayla’s parents are of Pakistani descent and consanguineous. Her mother, 37, had had three previous pregnancies with babies with CRIM-negative infantile onset Pompe disease. One of the pregnancies was electively terminated, one baby died at eight months, and another at 29 months. Genetic testing revealed Ayla had a disease-causing mutation called c.525_526del.
Doctors administered ERT with Lumizyme (at a dosage of 20 mg/kg of estimated fetal weight) starting at 24 weeks and five days of gestation and continued at two-week intervals. She received six infusions total.
When we were having Ayla, we didn’t know if she’d be able to walk. We didn’t know if she’d be able to talk. We didn’t know if she’d be able to eat. We didn’t know if she’d be able to laugh. So, as she hits each of these milestones, we continue to be amazed at her progress … she’s a miracle.
Once she was born, Ayla was given immunotherapy to help manage her immune response to ERT. This consisted of rituximab as well as intravenous immunoglobulin (IVIG). At almost 10 months, the Lumizyme was increased to 40 mg/kg/dose every two weeks and then administered weekly at 11 months. No side effects to any of the six infusions in the mother or the child were reported.
The levels of creatine kinase, a marker of long-term muscle damage, were normal from birth up to 13 months when they were evaluated by researchers. This contrasted with data from four CRIM-negative patients who all had elevated creatine kinase levels before receiving ERT, the scientists noted.
Ayla shows age-appropriate development
No movement problems were observed and Ayla showed “age-appropriate gross and fine motor development, muscle tone, and power,” the team wrote. She could walk independently at 11.5 months. Her echocardiograms — scans of the heart — were normal.
The researchers also tested the urinary levels of glucose tetrasaccharide (Glc4), a biomarker of accumulated glycogen. After birth, Glc4 levels were similar to those of a group of patients with CRIM-positive infantile-onset Pompe disease and two CRIM-negative infantile-onset Pompe disease patients. However, Aylas’s levels decreased quickly after postnatal ERT and are now considered normal. No glycogen deposits were detected in the placenta.
“Our results are consistent with in utero ERT attenuating or even halting the disease process in the fetal period,” the researchers wrote. “Furthermore, although it is accepted that starting treatment as early as possible improves outcomes in patients with lysosomal storage diseases (e.g., when the diagnosis is established after newborn screening), our results suggest that moving the window for therapeutic intervention into the prenatal period may further improve postnatal outcomes.”
The researchers said their Phase 1 clinical trial will continue to collect safety and efficacy data on in-utero ERT in a larger patient group. UCSF also received regulatory clearance to start using in-utero ERT in mucopolysaccharidosis types 1, 2, 4a, 6 and 7, Gaucher disease types 2 and 3, and Wolman disease.
“Enzyme replacement therapy is a new frontier in the field of fetal therapy; it has been exciting to see it grow from a research project in my laboratory to impact the outcome for this family ultimately. UCSF is considered the birthplace of fetal surgery, and it is a special privilege for us to continue to expand the technologies and treatments available to help families facing a difficult diagnosis during pregnancy,” MacKenzie said.
In an accompanying editorial, “Prenatal Enzyme Replacement Therapy,” Ans T. van der Ploeg, MD, PhD, noted that further follow-up of Ayla will be important.
“The outcomes of this trial are keenly awaited. In the meantime, the developmental course of the current patient is encouraging,” wrote van der Ploeg, who is chair of the Center for Lysosomal and Metabolic Diseases at Erasmus MC University, the Netherlands.
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