A new study led by UCL, the KK Women’s and Children’s Hospital and National University Health System in Singapore discovered that a fatal neurodegenerative condition known as Gaucher disease can be prevented in mice following fetal gene therapy. The study shows that the potential of fetal gene therapy to prevent and cure neonatal lethal neurodegenerative diseases in humans in utero.

Gaucher disease is an irreversible, inherited genetic metabolic disorder that results from not having enough glucocerebrosidase (GCase)-an enzyme that breaks fatty chemicals called glucocerebrosides (GBA). Because the body cannot break down this chemical, the fat-laden Gaucher cells build up in the spleen, liver, bone marrow, and nervous system, causing bone disease, anaemia, fatigue, eye problems, seizures, and brain damage.

Mutations in the GBA gene, which encodes the GCase enzyme that is deficient in Gaucher disease, are also a risk factor for Parkinson’s disease. Scientists used a viral vector to deliver genetic material into the brains of fetal mice carrying neuropathic Gaucher disease, caused by mutations in GBA. Mice who received the gene therapy exhibited less brain degeneration and survived considerably longer than untreated mice.

They discovered that mice who received an injection of adeno-associated virus (AAV) vector were more able to break down fatty chemicals and re-express the gene encoding an enzyme that is deficient in Gaucher disease. The mice who received the injection in utero, lived for up to 18 weeks after birth compared to 15 days in untreated mice and had no signs of neurodegeneration and were fertile and fully mobile.

Given the promising results shown in mice, the team from Singapore performed the test in non-human primates (NHP) at the early stages of pregnancy. This is the gestation when a clinical diagnosis of genetic conditions can be made, and when the immune system is more responsive to gene therapy. The research involved the use of NHPs due to their similarity to humans in the development of the central nervous system, and other organs, allowing for an accurate model to be achieved in fetal gene transfer.

The team showed that the delivery of viral vectors to the developing brain is feasible using an established clinical approach that resulted in the distribution of the transgene to the developing brain. Macaques and humans share a very similar neurological, immunological and physiological developmental time-line in the womb, making them accurate models for pre-clinical investigations before clinical trials can proceed. This can correct Gaucher disease and for other inborn errors of metabolism that can potentially be treated using fetal gene therapy.

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