Fetal Gene Therapy Prevents the Fatal Form of Gaucher's Disease

Scientists successfully administered gene therapy directly to the fetal brain of unborn mice to treat a deadly neuropathic form of the genetic metabolic disorder, Gaucher Disease (GD). Tests in the mouse model of neuropathic GD have shown that a single fetal intracranial injection of an adeno-associated viral vector (AAV) carrying gene (GBA) for glucocerebrosidase (GCase) lacked the production of Enzymes in the brain, which slowed down neurodegeneration, and allowed the mice to survive after birth, and even reproduce. The team has also demonstrated the ability to deliver vectors directly to target areas of the brain in a fetal non-human primate, the macaque.

"This new approach will bring hope not only for GD, but also for other innate errors in metabolism that can potentially be treated using fetal gene therapy," says Jerry Chan, Ph.D., Associate Professor and Senior Consultant, Department of Reproductive Medicine, KK Women & Children's Hospital, Singapore, who is co-author of the article published by the team in Nature Medicine entitled "Fetal Gene Therapy for Neurodegenerative Diseases of Infants". [19659002GDestunemaladiegénétiquehéréditaireirréversiblecauséepardesmutationsdugèneGBAcequisignifiequelescellulesneproduisentpasl'enzymelysosomaleGCasequiestnormalementresponsabledeladégradationdeslipidesglucocérébrosidiquesLescellulesdeGauchers'accumulentdanslaratelefoielamoelleosseuseetlesystèmenerveuxcausantdesmaladiesosseusesdel'anémiedelafatiguedesproblèmesoculairesdescrisesépileptiquesetdeslésionscérébralesThérapiederemplacement"Chezlespatientsadulteslaformelapluslégèreprésenteunehépatomégalieunesplénomégalieetparfoisunemaladiepulmonaireetosseuse"expliquentlesauteursEnrevanchelaformeaiguëdel'nGDchezlesenfantsentraîneuneneurodégénérescenceprécoceetirréversiblequiestlétaleetincurablecarl'enzymeadministréenepeutfranchirlabarrièrehématobrain

"Being able to provide as soon as possible therapy is essential to treat the brain that a limited ability to regenerate, "said Ahad Rahim, Ph.D., lecturer in translational neuroscience, at University College. London (UCL) School of Pharmacy.

The researchers developed a human AAV-GBA gene therapy construct, which they delivered directly into the brain of mouse nGD fetuses. Encouragingly, while untreated control animals developed neurodegenerative symptoms that led to death at day 15 postnatal, animals treated in utero all appeared normal, fertile, and had normal levels of GCase activity in the body. brain. "We found that mice given an adeno-associated vector injection (AAV) were more able to break down fatty substances and re-express the gene encoding an enzyme deficient in Gaucher disease," says Simon Waddington, author correspondent, MD, reader in gene transfer technology and acting director of the UCL Institute for Women's Health. "Mice that received injection in utero, lived up to 18 weeks after birth compared to 15 days in untreated mice and had no evidence of neurodegeneration and were fertile and fully mobile.

Other tests have shown that intravenous administration to newborn animals rather than to fetuses also resulted in some benefits, but postnatal therapy does not occur. was not as effective as direct intracerebroventricular administration in utero. "Neonatal intervention also saved mice but less effectively," adds Dr. Waddington.

Normalization of the activity of GCase in the brain after intracerebroventricular utero did not completely eliminate the pathology because the treated animals developed visceral disease.The intracerebroventricular administration did not prevent Gaucher cell infiltration into the spleen, liver and lungs, while postnatal intravenous therapy prevented enlargement of the spleen and infiltration of the Gaucher cell into the spleen , liver and lungs. ", Write the authors." However, intravenous administration effectively limits both neurological and visceral pathology.

In a final set of experiments, the team successfully used transabdominal ultrasound to guide delivery. A viral vector AAV9 fluorescence marker directly to the ventricles of the fetuses of macaque fetuses, demonstrating the potential to perform direct delivery of gene therapy to the fetal brain in a pattern that more closely reflects humans. "Macaques and humans share a neurological, immunological and physiological timeline similar to development in the uterus, making them precise models for preclinical studies before clinical trials can continue," says Dr. Chan. "We used a clinically relevant method to effectively deliver the GBA gene using AAV vectors for the brain."

"The generalized delivery of genes to the central nervous system by intracranial fetal injection provides the best therapeutic potential for early hereditary neurodegenerative diseases affecting the entire brain, "say the authors. "… the data on non-human primates provide a clinically feasible protocol for its implementation.This study, along with other preclinical studies on fetal gene therapy, meet the requirements suggested by the Advisory Committee on NIH recombinant DNA, namely safety and efficacy in relevant models for progression to clinical trials. "