SHANK3

A non-interventional study published in Frontiers in Psychiatry Psychometric profile characterization of 30 subjects with Phelan-McDermid Syndrome (PMS), defining three distinct subsets Study provides clinical scales and thresholds for patient selection in future clinical trials, based on aggressiveness, cognition, and behavioral traits Conducted in collaboration with the Medical and Molecular Genetics Institute (INGEMM) and the Research Institute La Paz Hospital (IdiPaz) in Madrid MADRID, SPAIN and CAMBRIDGE, MA, UNITED STATES, March 5th, 2025 - Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the final results of an observational clinical study aimed at psychometrically characterizing individuals with Phelan-McDermid syndrome (PMS) carrying deletions or pathogenic variants in SHANK3 have been published online in the journal Frontiers in Psychiatry. The purpose of this study was to gather data that could serve as a foundation for a future precision psychiatry clinical trial involving vafidemstat for this patient population. Agitation and aggression are key components of PMS, and vafidemstat has demonstrated efficacy in reducing agitation and aggression in a basket trial involving patients with Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), and Borderline Personality Disorder (BPD). This characterization paves the way for addressing these symptoms in a subset of PMS patients, further expanding the potential application of vafidemstat in reducing aggression in this specific patient population. Dr. Jordi Xaus, Oryzon’s CSO, stated, “The publication of these results in this prestigious clinical psychiatry journal marks a critical first step toward establishing vafidemstat as a novel personalized medicine therapy for relevant psychiatric indications. In recent years, a range of monogenic rare neurodevelopmental disorders linked to alterations in the epigenetic machinery and other key neuronal genes have been identified as potential targets for precision medicine. The use of LSD1 inhibitors has been shown to partially or fully rescue the complex phenotypes caused by these genetic mutations. Vafidemstat is currently the only LSD1 inhibitor in clinical development in CNS and represents a promising opportunity for these patients.” Dr. Julian Nevado, first author of the study and Head of Structural and Functional Genomics at INGEMM said “There is currently no treatment approved specifically for Phelan-McDermid syndrome. This study is a proof of concept that highlights the importance of patient stratification in PMS. Selecting PMS patients for a clinical trial based on their distinctive clinical and genetic characteristics will be essential in the era of personalized precision medicine.” In this pilot study, we clinically characterized the profile of 30 subjects, all diagnosed of molecularly confirmed PMS, by applying different psychometric scales, including Repetitive Behavior Questionnaire (RBQ), Vineland Adaptive Behavior Scales, ADOS-2, the Battelle developmental inventory screening test and the Behavior Problems Inventory (BPI). As reported in the publication, unsupervised hierarchical clustering of the collected psychometric data identified three groups of patients, with different cognitive, aggression and behavioral profile scores. Statistically significant differences in deletion sizes were detected comparing the three clusters (corrected by gender), and the size of the deletion appears to be correlated with some of the assayed scores. A link to access the online publication can be found here. Oryzon is developing vafidemstat in prevalent multifactorial psychiatric indications like BPD, with a Phase III trial in preparation, or schizophrenia, with the ongoing EVOLUTION Phase IIb trial, but is also committed to exploring the potential of vafidemstat in rare monogenic psychiatric and neurodevelopmental disorders such as PMS or Kabuki Syndrome. In the Phase IIb PORTICO trial in BPD, vafidemstat demonstrated nominal statistical significance in reducing agitation and aggression, also a relevant feature of some PMS patients and a significant caregiver burden that often results in sedation or institutionalization of these PMS patients. This published study provides relevant data for patient inclusion in a future clinical study exploring vafidemstat actionability for SHANK3-associated psychiatric disorders, including PMS, constituting a good example of how precision medicine may open new avenues to understand and treat Central Nervous System (CNS) disorders, pioneering individual management in PMS.

The company recently conducted a Type C meeting with the U.S. Food and Drug Administration (FDA) and is cleared to proceed with dosing of pediatric patients (2+ years) with JAG201 with expansion into adults (18+ years) following the pediatric cohort The first gene therapy clinical trial to evaluate therapeutic impact in a genetic form of autism and Phelan-McDermid syndrome. Site initiation to begin immediately and patient enrollment anticipated in Q12025. There are currently no treatments for the ~46,000 individuals in the U.S. with autism due to SHANK3 haploinsufficiency and those diagnosed with Phelan-McDermid syndrome JAG201 has been granted Rare Pediatric Disease designation and Fast Track designation by the FDA LAKE FOREST, Ill.--(BUSINESS WIRE)-- Jaguar Gene Therapy, a clinical-stage biotechnology company accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations, today announced the receipt of U.S. Food and Drug Administration (FDA) responses from a Type C meeting regarding the Phase I clinical trial for JAG201, a gene replacement therapy that targets a genetic form of autism spectrum disorder (ASD) where a SHANK3 mutation or deletion is present, and Phelan-McDermid syndrome. Specifically, the company received the FDA’s agreement to administer JAG201 to both pediatric and adult patients. Jaguar Gene Therapy plans to dose the first pediatric patient in Q1 of 2025 with expansion into adults following the pediatric cohort. “We are pleased to have reached agreement with the FDA to dose both pediatric and adult patients in our initial Phase I clinical trial of JAG201. Our preclinical data suggest that the administration of the gene therapy early in life provides a clear potential for benefits to be realized,” said Joe Nolan, CEO of Jaguar Gene Therapy. “Our hope is that potential early success in the pediatric population will open the door to evaluating JAG201 in broader patient populations. We look forward to continuing to work with the FDA, key opinion leaders and advocacy organizations in our efforts to bring forward a gene therapy treatment for autism spectrum disorder due to SHANK3 haploinsufficiency and genetically confirmed Phelan-McDermid syndrome.” “I think intervening earlier in a patient’s course of illness to address the underlying deficits caused by the SHANK3 deficiency while individuals are still actively undergoing development will provide a greater potential for benefit,” said Alexander Kolevzon, M.D., Professor of Psychiatry and Pediatrics at the Icahn School of Medicine at Mount Sinai. “There is an incredibly high unmet need among people living with Phelan-McDermid syndrome, and we expect there will be many eligible patients to participate in this important clinical trial.” JAG201 delivers a functional SHANK3 minigene via an adeno-associated virus serotype 9 (AAV9) vector to target neurons in the central nervous system. The therapy is administered via a one-time unilateral intracerebroventricular (ICV) injection, targeting the entire brain and spinal cord. JAG201 is designed to transduce haploinsufficient neurons to provide proper SHANK3 levels and to durably restore the synaptic function required for learning and memory, which underlie appropriate neurodevelopment and maintenance of cognitive, communicative, social and motor skills. The program is exclusively licensed from Broad Institute of MIT and Harvard. Recently, the FDA granted Rare Pediatric Disease designation for JAG201. The designation is granted for products that treat serious and life-threatening rare pediatric diseases. Under this program, companies are eligible to receive a priority review voucher for a subsequent marketing application for a different product following approval of a product with Rare Pediatric Disease designation. The FDA has also granted Fast Track designation for JAG201 based on the potential for the therapy to address a high unmet medical need for patients living with ASD where a SHANK3 mutation or deletion is present, and Phelan-McDermid syndrome. Currently, there are no therapeutic treatments approved for SHANK3 haploinsufficiency. Fast Track status allows for enhanced communication and collaboration between the FDA and drug developers, potentially accelerating the delivery of treatments to patients. About SHANK3 haploinsufficiency in ASD and Phelan-McDermid syndrome SHANK3 haploinsufficiency leads to synaptic dysfunction, disrupting communication between nerve cells. It causes a reduction of several key receptors and signaling proteins at excitatory synapses, resulting in impaired synaptic formation and function. Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions and learning. SHANK3 haploinsufficiency causes Phelan-McDermid syndrome (also known as 22q13.3 deletion syndrome), a rare genetic disorder with an estimated prevalence of 1 in 10,000.1,2 Genetic sequencing studies indicate that SHANK3 mutations may be present in approximately 0.5%-0.69% of patients with ASD, equating to around 46,000 patients in the U.S., including approximately 10,000 pediatric patients under the age of 18, although diagnosed cases are perceived as low by clinical experts given the barriers of access and low adoption of genetic testing in the diagnostic journey of ASD.3,4,5,6 In the subset of ASD patients who also have moderate to profound intellectual disability (ID), the prevalence of SHANK3 mutations increases from less than 1% to 2.12%.3,7 About Jaguar Gene Therapy Jaguar Gene Therapy, LLC is a clinical-stage biotechnology company dedicated to accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations. The company is made up of a proven team of experts who have first-hand experience in bringing novel gene therapy treatments to patients and their families. Jaguar is rapidly advancing an initial pipeline of three programs. The company’s lead program targets severe neurodevelopmental disorders caused by SHANK3 haploinsufficiency, due to loss of function mutations or deletions in SHANK3 including a genetic form of autism spectrum disorder and Phelan-McDermid syndrome. A clinical trial in pediatric patients is planned to begin in Q1 of 2025. The second pipeline program targets Type 1 galactosemia and the third targets Type 1 diabetes. Jaguar’s key investors include Deerfield Management Company, ARCH Venture Partners and Eli Lilly and Company. For more information, please visit and follow Jaguar Gene Therapy on LinkedIn. References 1. Costales JL et al. Neurotherapeutics 2015; 12 (3): 620–630. 2. What is Phelan-McDermid syndrome? Available at: . Accessed January 2023. 3. Betancur C et al. Mol Autism 2013; 4 (1): 17. 4. Jaguar Gene Therapy market research, 2022; data on file. 5. 6. 7. Leblond CS et al. PLoS Genet 2014; 10 (9): e1004580. Disclosure Dr. Alexander Kolevzon has served as a paid consultant for Jaguar Gene Therapy.

In an important step toward more effective gene therapies for brain diseases, researchers have engineered a gene-delivery vehicle that uses a human protein to efficiently cross the blood-brain barrier and deliver a disease-relevant gene to the brain in mice expressing the human protein. Because the vehicle binds to a well-studied protein in the blood-brain barrier, the scientists say it has a good chance at working in patients. In an important step toward more effective gene therapies for brain diseases, researchers from the Broad Institute of MIT and Harvard have engineered a gene-delivery vehicle that uses a human protein to efficiently cross the blood-brain barrier and deliver a disease-relevant gene to the brain in mice expressing the human protein. Because the vehicle binds to a well-studied protein in the blood-brain barrier, the scientists say it has a good chance at working in patients. Gene therapy could potentially treat a range of severe genetic brain disorders, which currently have no cures and few treatment options. But FDA-approved forms of the most commonly used vehicle for packaging and delivering these therapies to target cells, adeno-associated viruses (AAVs), aren't able to efficiently cross the blood-brain barrier at high levels and deliver therapeutic cargo. The enormous challenge of getting therapies past this barrier -- a highly selective membrane separating the blood from the brain -- has stymied the development of safer and more effective gene therapies for brain diseases for decades. Now researchers in the lab of Ben Deverman, an institute scientist and senior director of vector engineering at the Broad, have engineered the first published AAV that targets a human protein to reach the brain in humanized mice. The AAV binds to the human transferrin receptor, which is highly expressed in the blood-brain barrier in humans. In a new study published in Science, the team showed that their AAV, when injected into the bloodstream in mice expressing a humanized transferrin receptor, crossed into the brain at much higher levels than the AAV that is used in an FDA-approved gene therapy for the central nervous system, AAV9. It also reached a large fraction of important types of brain cells, including neurons and astrocytes. The researchers then showed that their AAV could deliver copies of the GBA1 gene, which has been linked to Gaucher's disease, Lewy body dementia, and Parkinson's disease, to a large fraction of cells throughout the brain. The scientists add that their new AAV could be a better option for treating neurodevelopmental disorders caused by mutations in a single gene such as Rett syndrome or SHANK3 deficiency; lysosomal storage diseases like GBA1deficiency; and neurodegenerative diseases such as Huntington's disease, prion disease, Friedreich's ataxia, and single-gene forms of ALS and Parkinson's disease. "Since we came to the Broad we've been focused on the mission of enabling gene therapies for the central nervous system," said Deverman, senior author on the study. "If this AAV does what we think it will in humans based on our mouse studies, it will be so much more effective than current options." "These AAVs have the potential to change a lot of patients' lives," said Ken Chan, a co-first author on the paper and group leader from Deverman's group who has been working on solving gene delivery to the central nervous system for nearly a decade. Mechanism first For years, researchers developed AAVs for specific applications by preparing massive AAV libraries and testing them in animals to identify top candidates. But even when this approach succeeds, the candidates often don't work in other species, and the approach doesn't provide information about how the AAVs reach their targets. This can make it difficult to translate a gene therapy using these AAVs from animals to humans. To find a delivery vehicle with a greater chance of reaching the brain in people, Deverman's team switched to a different approach. They used a method they published last year, which involves screening a library of AAVs in a test tube for ones that bind to a specific human protein. Then they test the most promising candidates in cells and mice that have been modified to express the protein. As their target, the researchers chose human transferrin receptor, which has long been the target of antibody-based therapies that aim to reach the brain. Several of these therapies have shown evidence of reaching the brain in humans. The team's screening technique identified an AAV called BI-hTFR1 that binds human transferrin receptor, enters human brain cells, and bypasses a human cell model of the blood-brain barrier. "We've learned a lot from in vivo screens but it has been tough finding AAVs that worked this well across species," added Qin Huang, a co-first author on the study and a senior research scientist in Deverman's lab who helped develop the screening method to find AAVs that bind specific protein targets. "Finding one that works using a human receptor is a big step forward." Beyond the dish To test the AAVs in animals, the researchers used mice in which the mouse gene that encodes the transferrin receptor was replaced with its human equivalent. The team injected the AAVs into the bloodstream of adult mice and found dramatically higher levels of the AAVs in the brain and spinal cord compared to mice without the human transferrin receptor gene, indicating that the receptor was actively ferrying the AAVs across the blood-brain barrier. The AAVs also showed 40-50 times higher accumulation in brain tissue than AAV9, which is part of an FDA-approved therapy for spinal muscular atrophy in infants but is relatively inefficient at delivering cargo to the adult brain. The new AAVs reached up to 71 percent of neurons and 92 percent of astrocytes in different regions of the brain. In work led by research scientist Jason Wu, Deverman's team also used the AAVs to deliver healthy copies of the human GBA1 gene, which is mutated in several neurological conditions. The new AAVs delivered 30 times more copies of the GBA1 gene than AAV9 in mice and were delivered throughout the brain. The team said that the new AAVs are ideal for gene therapy because they target a human protein and have similar production and purification yields as AAV9 using scalable manufacturing methods. A biotech company co-founded by Deverman, Apertura Gene Therapy, is already developing new therapies using the AAVs to target the central nervous system. With more development, the scientists think it's possible to improve the gene-delivery efficiency of their AAVs to the central nervous system, decrease their accumulation in the liver, and avoid inactivation by antibodies in some patients. Sonia Vallabh and Eric Minikel, two researchers at the Broad who are developing treatments for prion disease, are excited by the potential of the AAVs to deliver brain therapies in humans. "When we think about gene therapy for a whole-brain disease like prion disease, you need really systemic delivery and broad biodistribution in order to achieve anything," said Minikel. "Naturally occurring AAVs just aren't going to get you anywhere. This engineered capsid opens up a world of possibilities."