Advancing precision genetic therapies for rare neurodevelopmental disorders through CRISPR, prime editing, and translational neuroscience.
Neurogenetic disorders arise when changes in DNA interfere with the development or function of the nervous system. Many emerge in childhood, affecting learning, communication, movement, or seizure control, with lifelong consequences for families.Advances in genetic sequencing now allow researchers to identify disease-causing variants with increasing precision. Yet identifying a mutation is only the beginning. The challenge is understanding how genetic changes alter developing neurons—and whether those effects can be reversed.At the Garin-Shkolnik Lab at Rambam Health Care Campus, we work at the intersection of clinical research, molecular genetics, and therapeutic innovation. Our neurogenetic research prioritizes disease-modifying approaches: treatments designed to address an underlying biological cause rather than symptoms alone. A major focus is the development of CRISPR-based gene editing, including prime editing, for rare genetic neurodevelopmental disorders.
An important focus of our work is GRIN2B-related neurodevelopmental disorder, a rare condition caused by pathogenic variants in the GRIN2B gene. GRIN2B encodes GluN2B, a key component of the NMDA receptor, a protein complex essential for communication between neurons, synaptic plasticity, learning, and brain development.Changes in GRIN2B can disturb receptor activity and the formation of neuronal networks. Affected individuals may experience developmental delay, intellectual disability, limited speech, abnormal muscle tone, movement difficulties, autism-related features, or epilepsy. Disease severity varies substantially, even among individuals with variants in the same gene.Crucially, not all GRIN2B mutations behave alike. Some reduce the amount of functional protein produced; others create an altered protein that interferes with receptor function. These different mechanisms may require different therapeutic solutions. By studying GRIN2B in depth, we aim to establish principles that could inform treatment development for other genetically defined neurological conditions.
Our research follows a translational pathway that connects genetic findings with laboratory models and potential interventions. Patient-associated variants are studied in cellular systems, human stem-cell-derived neurons, three-dimensional brain organoids, and appropriate animal models. The models reveal how mutations act, when dysfunction emerges, and whether normal signaling can be restored.Rather than relying on a single therapeutic technology, we examine complementary genetic strategies. Gene supplementation seeks to supply a functional gene copy, while gene editing aims to modify the disease-causing DNA itself. Understanding the mutation's mechanism helps determine which approach warrants further investigation.
CRISPR technologies make it possible to direct molecular tools to selected locations in the genome. Conventional CRISPR-Cas9 editing uses a guide RNA to locate a DNA sequence and a Cas enzyme to cut it. Cellular repair processes can then be harnessed to modify the targeted region. Newer CRISPR-derived systems can achieve specific changes without requiring a conventional double-strand DNA break.The Garin-Shkolnik Lab's gene-editing research focuses on developing strategies to correct pathogenic variants underlying GRIN2B-related disease. Our goal is to move beyond simply identifying harmful mutations toward testing whether their genetic effects can be reversed in relevant experimental models.This involves designing and comparing editing systems, measuring the proportion of precisely corrected DNA, and checking for unintended changes. A successful edit must do more than improve a DNA sequence: it should also help restore the molecular and functional behavior of the affected neurons. We seek correction strategies matched to genetic variants and disease mechanisms.
Prime editing is a particularly promising direction in our research. Often described as a form of molecular search-and-replace, prime editing combines a modified CRISPR-associated protein with a reverse transcriptase enzyme and a specialized prime-editing guide RNA, or pegRNA. Together, these components direct a defined DNA change at a chosen genomic location.Unlike conventional CRISPR-Cas9 approaches that deliberately create double-strand breaks, prime editing is designed to write precise sequence changes without such a break or a separately supplied DNA repair template. In principle, it can correct multiple classes of small genetic errors, including certain substitutions, insertions, and deletions. Nevertheless, its performance depends on the genomic site, cellular context, and delivery system; precise editing must be demonstrated experimentally, not assumed.In GRIN2B research, we are investigating prime-editing strategies for distinct pathogenic variants affecting the same region of the gene. Examples include c.2065G>T (p.Gly689Cys) and c.2065G>A (p.Gly689Ser). Although both alter the same amino-acid position, they involve different DNA substitutions. Prime editing offers a potential way to design mutation-specific corrections while drawing upon a shared technology platform.We also explore approaches targeting regions of GRIN2B containing multiple disease-associated variants. Such approaches remain exploratory and require rigorous demonstration of feasibility, precision, and biological benefit.
Alongside prime editing, we evaluate base editing, a family of CRISPR-derived methods that chemically changes individual DNA bases without introducing a conventional double-strand break. Different base editors support different classes of nucleotide conversions, so the choice of editor must match the specific mutation.Comparing base editing with prime editing allows us to consider several routes to a corrected sequence. We also investigate the broader potential of CRISPR-based approaches for mutations involving reduced gene expression or gene disruption. No single editing method is suitable for every variant, and our research is designed around that biological reality.
Human disease models are essential for evaluating whether genetic correction produces meaningful effects. Working within a collaborative research network, we study neurons derived from induced pluripotent stem cells (iPSCs) carrying patient-specific GRIN2B variants. These cells can be differentiated into neuronal cultures and three-dimensional brain organoids that reproduce selected features of early human brain development.The models help researchers examine neuronal maturation, synaptic organization, electrical activity, and network communication. They also provide a setting in which corrected and uncorrected cells can be compared under controlled conditions.Advanced methods—including electrophysiology, calcium imaging, molecular profiling, and gene-expression analysis—help connect genetic changes to neuronal function. Organoids are not complete miniature human brains, and findings in them cannot establish clinical effectiveness. They are, however, valuable tools for prioritizing promising therapeutic candidates before more extensive preclinical studies.
One of the greatest challenges in treating neurogenetic disorders is delivery. The blood-brain barrier protects the brain but also limits the movement of many therapeutic molecules from the bloodstream into nervous tissue. Even a highly precise editor will not be useful if it cannot reach the appropriate cells at a safe and effective dose.Our translational program therefore explores delivery approaches suitable for genetic therapies targeting the central nervous system. These include engineered adeno-associated viral (AAV) vectors and lipid nanoparticles (LNPs). AAV systems can support gene delivery to neurons, while lipid-based systems offer different possibilities for transporting RNA and gene-editing components. Each platform involves trade-offs in cargo capacity, cell targeting, durability, and safety.We are especially interested in how delivery technologies might accommodate the relatively large components of prime-editing systems. Optimizing delivery, limiting unintended editing, controlling exposure, and evaluating long-term safety are essential steps before any application in people could be considered.
Gene editing is one part of a broader effort to develop genetic treatments for GRIN2B-related disorders. In close collaboration with Prof. Shai Berlin at the Technion, a complementary research program investigates gene supplementation: introducing a functional copy of GRIN2B into neurons rather than rewriting the existing variant.The Berlin team has demonstrated preclinical delivery and expression of full-length GRIN2B using engineered AAV vectors, including delivery to the brain following systemic administration in animal models. This is an important proof of concept, particularly because the gene's large size creates technical challenges for viral packaging.Together, these approaches allow comparison of therapeutic mechanisms and their suitability for different mutations. The preclinical gene-delivery results do not yet establish clinical benefit or an available treatment.
Neurogenetic disorders demand close cooperation among patients, clinicians, molecular biologists, neuroscientists, and gene-delivery specialists. Our laboratory contributes clinical and translational leadership, coordinates with patient and research networks, and advances the gene-editing component of a multidisciplinary GRIN2B program.Together with Prof. Berlin, Dr. Tali Garin-Shkolnik received an Israel Science Foundation MAVRI biomedical research grant, announced in July 2026, supporting research into complementary GRIN2B treatment strategies. Our work is also connected with 2BCured, a parent-led research network committed to accelerating the development of therapies for GRIN2B-related neurodevelopmental disorder.Responsible translation requires careful evaluation of editing specificity, off-target effects, delivery, dosage, and functional outcomes. We distinguish promising laboratory findings from proven treatments and regard clinical application as a future goal requiring substantial additional research and regulatory review.
Our long-term vision is to help transform the diagnosis of a neurogenetic disorder from an explanation of symptoms into a starting point for targeted treatment development. By combining CRISPR, prime editing, patient-derived disease models, and translational collaboration, we aim to build a foundation for therapies that address disease-causing variants at their source.
Our mission is to turn precise genetic knowledge into carefully validated therapeutic possibilities—and, ultimately, better options for individuals and families affected by rare neurodevelopmental disorders.