In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease

Abstract

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Figure 1.. Case Presentation and Skeletal-Muscle and Cardiac Outcomes.

Panel A shows the family pedigree. Squares indicate male family members, circles female family members, triangles pregnancies not carried to term, double bars consanguinity, open symbols unaffected, filled black symbols affected, and diagonal slashes deceased. CRIM denotes cross-reactive immunologic material, IOPD infantile-onset Pompe’s disease, and neg negative. Panel B shows creatine kinase levels at 4 days or more of life in patients with CRIM-negative IOPD (gray dashed curves) treated after newborn screening (NBS) (treated at ≤4 weeks of age) as compared with the levels in Sibling 3 (green). IUERT denotes in utero enzyme-replacement therapy. Panel C shows fetal echocardiograms, four-chamber (a and c) and short-axis (b and d), of Sibling 2, who was untreated (top row), and Sibling 3, who received IUERT (bottom row) performed at 34 weeks of gestation. The ventricular-wall thickness, quantified as diastolic measurement of the interventricular septum (IVSd) (asterisk), was 5.7 mm (z score, 7.0) in Sibling 2, whereas it remained normal in S ibling 3 (3.4 mm; z score, 0.6) during fetal therapy. The z scores were calculated according to the methods of Firpo et al. LV denotes left ventricle, and RV right ventricle. Panel D shows the left ventricular mass index in Sibling 3 (green) as compared with patients with CRIM-negative IOPD treated after NBS (gray dashed curves) and the patient’s two previous affected siblings (Siblings 1 [orange] and 2 [purple]). The first data point for Sibling 1 is just before the initiation of enzyme-replacement therapy (ERT), and the plot shows prolonged time to improvement; Sibling 2 never received ERT.

Figure 2.. Placental Pathological Analysis.

Panel A shows electron microscopic images from previously studied patients with IOPD who did not receive IUERT^, (left column) and from the current patient, who received IUERT (right column). The top row shows numerous membrane-bound glycogen lobules (L) in a stromal cell as well as unbound cytoplasmic glycogen rosettes (black arrow) in the untreated patient, which are not present in the patient who received IUERT. The bottom row shows that the capillary endothelium and pericytes contain glycogen-filled lysosomes (asterisks) in a fetus with IOPD, which are not present in the current patient. Panel B shows periodic acid–Schiff (PAS) staining (without diastase digestion) of placental villi. The top row shows photomicrographs from an untreated IOPD placenta at term with PAS-positive granules throughout, which are not present in the current patient (middle row) or the healthy unaffected placenta (bottom row) at a gestational age similar to that of the current patient at term. The right column of images shows the same at higher magnifications; the red arrow highlights PAS-positive granules.

Figure 3.. (facing page). Laboratory Monitoring.

Panel A shows the time course for antidrug antibody levels and immune tolerance induction in the current patient (Sibling 3, green; left graph) and the proband (Sibling 1, red; right graph). The antidrug antibody levels of Siblings 1 and 3 reached the same peak, with Sibling 1 having a longer duration of titers at this level. Sibling 3 received immune tolerance induction as previously published, followed by monthly rituximab alone, then rituximab alone every other month, and later every 3 months; Sibling 1 received immune tolerance induction as previously published, followed by a repetition of a full course of immune tolerance induction (three medications), owing to her persistent titers at 1:6400. Pharmacokinetic and clinical concerns are present when titers reach a level of 1:12,800 or greater.^, IVIG denotes intravenous immune globulin. Panel B shows plasma trough levels of acid α-glucosidase (GAA) enzyme activity (obtained before each ERT infusion) in Sibling 3’s fetal plasma over the course of IUERT. Panel C shows glucose tetrasaccharide (Glc₄) levels in amniotic fluid samples for Sibling 3 (green) over the course of IUERT infusions as compared with the levels for gestational age–matched unaffected controls (gray). These findings show concordance with unaffected controls and a rise in the levels of this biomarker with older gestational age. Panel D shows the Glc₄ levels in neonatal urine samples obtained postnatally from Sibling 3 (green), as compared with baseline values in a previously studied CRIM-positive cohort in the neonatal period at less than 1 month of age (light blue) and with values in patients with CRIM-negative IOPD (gray dashed curves) treated after NBS (treated at ≤4 weeks of age). Cr denotes creatinine, and pos positive.