# Phase 1 Study of In Utero Enzyme Replacement Therapy for the Treatment of Lysosomal Storage Diseases

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $666,314

## Abstract

Lysosomal storage disorders (LSDs) are severe diseases arising from mutations in critical enzymes and
collectively have an estimated incidence of 1 in 5,000 to 1 in 5,500 live births. Patients with LSDs are at
increased risk of serious perinatal morbidity and mortality, with some not even surviving to birth. The current
treatment for pediatric patients, enzyme replacement therapy (ERT), is limited by three aspects: the
progressive development (sometimes in utero) of organ-specific manifestations, the development of anti-ERT
antibodies, and the inability of ERT to cross the blood-brain barrier to address neurologic effects. Thus, there is
an unmet medical need to develop more effective therapies for patients with LSDs, starting before birth. In a
mouse model of mucopolysaccharidosis type 7 (MPS7), we showed that in utero ERT (IUERT) followed by
postnatal ERT improved survival, crossed the blood-brain barrier, ameliorated disease, and induced tolerance
to the ERT. Based on these results, we obtained an IND to perform a first-in-human, non-randomized, single
site phase 1 clinical trial of IUERT and seek funding to support this clinical trial. Since each individual LSD is
rare, but they share similar pathophysiology, we have included eight different LSDs (and their specific ERT)
under this protocol: MPS Types 1, 2, 4a, 6, and 7, Infantile-onset Pompe Disease (IOPD), Neuronopathic
Gaucher (Types 2 and 3), and Wolman disease. We will enroll 10 maternal-fetal pairs for infusion of the ERT
via the umbilical vein every 2-4 weeks, starting after 18 weeks of gestation. We will evaluate the safety and
feasibility of this prenatal therapy, as well as the efficacy of ERTs in resolving fetal manifestations (if present)
and improving long-term outcomes including neurologic and cardiac function, mobility, and growth. (Aim 1). We
will also examine the pharmacokinetics and pharmacodynamics of IUERT by evaluating enzyme trough levels
throughout gestation, as well as levels of disease-specific lysosomal accumulations before and after birth (Aim
2). Finally, we will evaluate whether in utero exposure to the recombinant enzyme will induce tolerance, as
determined by lack of anti-drug antibodies and generation of enzyme-specific regulatory T cells (Aims 3). In the
past year, our team has successfully treated a fetus with IOPD (whose two previous siblings had severe
cardiomyopathy and suffered perinatal demise); this patient was born at term after multiple prenatal enzyme
infusions and has normal cardiac function. We have assembled a multidisciplinary team and partnered with
several experts on biochemical analyses for LSDs. Since we anticipate identifying fetuses based on a known
family history, we have also been collaborating with multiple national and international patient advocacy groups
to include patients and families in the design and execution of this trial. We conducted a parent survey to
evaluate their attitudes and found that the majority of respondents would c...

## Key facts

- **NIH application ID:** 10707992
- **Project number:** 5R01HD110270-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Tippi Mackenzie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $666,314
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707992

## Citation

> US National Institutes of Health, RePORTER application 10707992, Phase 1 Study of In Utero Enzyme Replacement Therapy for the Treatment of Lysosomal Storage Diseases (5R01HD110270-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10707992. Licensed CC0.

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