Our Research

Research Mission

We translate research discoveries into clinical tools to help patients.

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Precision Diagnostics

BETTER, FASTER, ACTIONABLE

Using the most advanced gene sequencing technology, we are discovering the fetal genes that drive abnormalities that begin in utero, including hydrops fetalis. We bring next generation sequencing to real patients with unexplained ultrasound abnormalities to reveal genetic etiologies that elude standard genetic testing.

Patients benefit from the collective clinical and research experience of a multi-disciplinary team drawn from experts in molecular medicine, genetics, genomics, bioinformatics, bioethics, and many clinical specialties. We anticipate that rapid exome sequencing will become a standard diagnostic tool to manage pregnancy complications and to identify genetic abnormalities that will be treatable with fetal molecular therapies currently in development

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Non-immune hydrops fetalis (NIHF) is a condition in pregnancy marked by abnormal collections of fluid in the fetus. It carries significant risks of stillbirth during the pregnancy, as well as of early delivery, serious illness and death for the newborn, and a maternal complication called mirror syndrome.

Photo of Hydrops ultrasound
Ultrasound indicates hydrops

NIHF can result from genetic abnormalities, birth defects, and viruses. The cause of NIHF in over half of all affected pregnancies remains unknown after standard testing, but our approach with exome sequencing reveals the cause for many of these. Without an understanding of the reason for the NIHF, prenatal care for a pregnancy with NIHF is less focused, clear plans for newborn care cannot be made, and the chance of NIHF happening again in a future pregnancy cannot be accurately estimated.

Our goals are to develop a precision-based approach to the diagnosis and care for NIHF in order to improve both newborn and maternal outcomes. Ultimately, our group aims to develop novel, specific in utero treatments for each underlying cause of NIHF.

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Fetal Molecular Therapies

Expanding the Repertoire of Fetal Therapy

The fetal environment provides an extraordinary opportunity for definitive treatment of genetic diseases. The immune privilege of the fetus enables the induction of tolerance to stem cells from different donors or to missing proteins. The fetus does not mount an immune response to new viral vectors. Most importantly, treatment before the blood-brain barrier closes can allow us to treat devastating neurologic diseases more effectively than after birth. By putting together a team of genome scientists, clinicians, ethicists, and rare diseases experts, the Center is harnessing the strengths of the UCSF community to catalyze a new era in fetal therapy.

The FDA approved the first Investigational New Drug (IND) application for in utero stem cell transplantation, using maternal-derived hematopoietic stem cells to treat fetuses with alpha thalassemia major.

We are performing the world’s first clinical trial of in utero transplantation in fetuses with alpha thalassemia major. Other indications for in utero stem cell transplantation include patients with similar hemoglobin disorders, Fanconi Anemia. Moreover, based on the understanding that fetal exposure can tolerize to specific donors, this strategy can also be used to prepare fetuses who will ultimately need a kidney transplant from a parent. Fetuses with lysosomal storage disorders could also be treated with HSC transplantation, since healthy blood cells can cross-correct the disease in multiple organs such as the brain and liver. We also have an International Registry of Patients with Alpha Thalassemia (ATM Registry).

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In utero transplanted stem cells cross into the brain and become microglia

Infants with lysosomal storage disorders such as Pompe disease are born with irreversible damage in multiple organs such as the heart and brain; they also develop immune reactions to replacement enzymes after serial infusions. Preclinical studies, including our studies of fetal enzyme replacement to treat MPS7, suggest that providing the enzyme before birth can circumvent these issues.

In 2020, the FDA approved our IND application for the Prenatal Enzyme Replacement for Lysosomal Storage Diseases (PEARL) Trial for fetuses diagnosed with any of eight lysosomal storage diseases. A case report regarding the first patient treated using the IUERT clinical protocol, developed by Tippi MacKenzie and colleagues at UCSF, was published in the New England Journal of Medicine in November 2022.

A phase 1 clinical trial of enzyme replacement therapy to treat a lysosomal storage disorder before birth is underway at UCSF. We also have a registry of patients diagnosed with lysosomal storage diseases (LSD Registry).

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In Utero Gene Therapy Think Tank group photo
In Utero Gene Therapy Think Tank, November 18, 2019, San Francisco

With the recent success of gene therapies for hemophilia and spinal muscular atrophy, we are leading an international effort to perform safe and ethical genetic therapies for fetuses with genetic diseases thalassemias, hemophilia, and metabolic syndromes. Emerging gene editing techniques will likely enable more precise and safer editing for some diseases. To this end, we endeavor to lead the discussion regarding the ethical, scientific, and clinical aspects of fetal genetic therapies.

CERSI-FDA Workshop on Prenatal Somatic Cell Gene Therapies, October 2021, Virtual
In Utero Gene Therapy Think Tank, November 2019, San Francisco

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