A roughly $40 million National Institutes of Health (NIH) grant awarded to Yale School of Medicine will support the development of a gene-editing platform technology capable of reaching the human brain. The innovative new genome-editing technology, which was developed from the first phase of the NIH Common Fund Somatic Cell Genome Editing (SCGE) program, could potentially lead to treatments or cures for many neurogenetic diseases. If we can prove the concept of this technology in the two diseases we’re studying, we can then apply it to hundreds or thousands of diseases of the brain.Yong-Hui Jiang, MD, PhD Neurogenetic disorders can be devastating, and treatments are scarce. The two-phase grant from the NIH will support research into a novel CRISPR-based gene-editing technology and delivery platform for targeting neurogenetic diseases. The grant will focus on Angelman syndrome and H1-4 syndrome as a proof-of-concept, and could be applicable to many neurogenetic disorders. The new delivery technology, known as STEP (Stimuli-responsive Traceless Engineering Platform), has the capacity to revolutionize genome-editing therapy and create a one-time treatment for a range of genetic disorders. The work will be led by Yong-Hui Jiang, MD, PhD, professor of genetics, of pediatrics and of neuroscience and chief of medical genetics, and Jiangbing Zhou, PhD, professor of neurosurgery and of biomedical engineering, both at Yale School of Medicine. The team also includes co-leader Elizabeth Berry-Kravis, MD, PhD, professor of pediatrics and neurological sciences and director of the RUSH Pediatric Neurosciences F.A.S.T. Center for Translational Research at RUSH University in Chicago; and Allyson Berent, DVM, DACVIM and Jennifer Panagoulias of the Foundation for Angelman Syndrome Therapeutics (FAST). The HIST1H1E foundation led by Kimberly Greenberg will also participate the study. The first $26.5 million grant will support pre-clinical and toxicology studies in animal models and human-brain organoids. If the milestones of the first phase are met, the NIH will provide an additional $13 million to fund clinical trials in humans. “If we can prove the concept of this technology in the two diseases we’re studying, we can then apply it to hundreds or thousands of diseases of the brain,” says Jiang. Existing gene therapy methods face limitations Until now, the development of gene-therapy technologies has been slow as researchers focus on one disease at a time. Furthermore, existing gene therapies commonly rely on viruses as the delivery vehicle, but this method has risks. The exposure of the body to viral proteins can trigger adverse reactions. Viruses can incorporate DNA into the human genome and increase risk for tumor development. Viruses may be particularly not ideal for delivery of genome-editing therapy due to a risk of off-target effects associated with long-term gene expression. While non-viral nanoparticle-based delivery platforms for genome editing options do exist, their delivery to the brain has been challenging due to many limitations. New platform utilizes ribonucleoproteins (RNPs) that directly access the brain At Yale, a joint team led by Jiang and Zhou invented the STEP technology and successfully applied it for delivery of genome editing therapy for treatment of various diseases in animal models. Instead of viruses, the novel platform utilizes a chemical engineering approach to achieve brain-wide delivery of gene-editing with high efficiency. “Over the past few years, we have been working on development of this technology. I am thrilled about the opportunity to bring it to the clinical bedside,” says Zhou. Through this new system, the team administers the delivery technology intrathecally, or through a spinal tap. Due to their unique physical chemical properties, STEP-RNPs demonstrate a great ability to penetrate the brain and edit neuronal cells with high efficiency. After entering the cells, RNPs are quickly degraded, limiting the risk of off-target effects. Other molecular therapies such as antisense oligonucleotides (ASOs) require frequent treatments, but this new technology could work as a single dose with a permanent effect and potentially with a greater efficiency than ASOs. A potential therapeutic platform for a range of brain diseases The team will be focused on Angelman syndrome and H1-4 syndrome because prior research already indicates significant promise of the benefits of gene-editing therapy in treating these conditions. But ideally, their strategy can be adopted for treating many other neurogenetic disorders as well. In particular, some neurogenetic conditions are rare diseases, so there is often little incentive for pharmaceutical companies to invest in therapeutics. The researchers hope their platform will increase these companies’ interest in investing because it can be applied to many different diseases. In May, Yale School of Medicine joined the NORD Rare Disease Centers of Excellence network. This work adds to a growing concentration of groundbreaking basic research, clinical translation, and clinical care in the rare disease space taking place at Yale School of Medicine. Other faculty participants for the projects from Yale School of Medicine include James McPartland, PhD; Julie Wolf, PhD; Michele Spencer-Manzon, MD; Hui Zhang, MD, PhD; Caroline Hendry, PhD; James Dziura, PhD, MPH; Nigel Bamford, MD; Kathleen Cardinale, MD; Caihong Qiu, PhD; and Eric Velazquez, MD. The NIH Federal Award Identification Number for the grant is UG3TR004713.