PALO ALTO, Calif. (April 5, 2023) – SynGAP Research Fund (SRF), a 501(c)(3) public charity whose mission is to improve the quality of life for SYNGAP1 patients through the research and development of treatments, therapies and support systems, today announced they have awarded a $130,000 collaborative grant to the lab of Xing Tang, PhD at Boston Children's Hospital & AXONIS Therapeutics to investigate the treatment effects of KCC2-enhancing small molecule compounds in SYNGAP1 haploinsufficiency.
Principal Investigator of translational neuroscience at AXONIS, Dr. Kadam, has been working with the SRF community for many years. While at Johns Hopkins, she gave a popular SRF Webinar on some of her SYNGAP1 research. “When Dr. Kadam joined AXONIS and asked if SRF would be interested in supporting some of their work, we agreed immediately,” said Michael Graglia, Managing Director of SRF. “Dr. Kadam’s commitment to helping patients is clear. Supporting AXONIS’ collaboration with Dr. Tang is about as good as it gets for a patient-family led organization. This is precisely the kind of work the Fund exists to support on behalf of the ~1,200 people we know who are currently living with this ultra rare disease, still without treatment or cure.”
The therapeutic target - KCC2
KCC2 is a neuron-specific, electroneutral chloride transporter that is essential for ensuring the activities of neurons in the brain can be inhibited when necessary. KCC2 extrudes chloride to maintain low chloride concentrations in neurons, which allows inhibition upon GABA receptor activation. In some neurodevelopmental disorders, KCC2 is downregulated leading to Excitatory/Inhibitory (E/I) imbalance within the neural network. Without KCC2, affected neurons no longer respond appropriately to inhibitory inputs, causing dysfunction in neural circuits and impaired neurological functions, such as pain, paralysis, spasticity, seizures and intellectual disabilities.
Treatments that enhance KCC2 to restore E/I balance have been shown to restore normal functions in several preclinical models of neurological disorders (e.g., Rett syndrome, epilepsies). Currently, no KCC2-enhancing drugs exist on the market.
The researcher - Dr. Tang
Dr. Tang is an Assistant Professor of Neurosurgery at Boston Children’s Hospital and Harvard Medical School. He received his Ph.D. in Neurobiology from Pennsylvania State University, and completed his postdoctoral training at the Whitehead Institute for Biomedical Research/MIT. His scientific interest has been focused on understanding the molecular and cellular basis of pediatric brain disorders in order to ultimately develop therapeutics that can be translated to the clinic to improve patient care. His work led to the discovery of the first group of small molecule compound drugs that stimulates KCC2 expression in neurons, which has shown promising results in rescuing disease-related phenotypes in human neuron and mouse models of Rett syndrome.
Dr. Tang said “We are very grateful to the SynGAP Research Fund for supporting this collaborative work between my lab and AXONIS. We will use SynGAP patient iPSC-derived human neurons provided by SRF partner, Rarebase, to test the feasibility of a novel therapeutic approach that restores KCC2 expression or activity to reduce the neural network hyperexcitability that causes seizures in the brains of SynGAP patients. I had a very special experience attending last year’s SRF-organized research conference and meeting with members of the SynGAP community. Their courage, enthusiasm and positive energy are contagious. It is the cherished hope of myself and my team that the work we do here in the lab can one day make a difference in the lives of SynGAP patients for the better.”
SRF Volunteer Minnie Zhou, DNP, CRNA, recalls “Dr. Tang and I met at the SRF conference in Nashville last year. He is an extremely approachable scientist who truly cares about helping children with SYNGAP1. He met my affected daughter and mentioned his daughter of a similar age and wished she were in attendance so they could play together. I am grateful SRF is funding researchers such as Drs. Tang and Kadam; both with such zeal about improving the lives of children with brain disorders.”
The company - AXONIS
AXONIS Therapeutics is advancing breakthrough drug discoveries to develop first-in-class therapies for neurological disorders, to make a real difference for patients, their families, and the global healthcare system. AXONIS’ oral KCC2 potentiator drugs restore excitation/inhibition balance to dysfunctional central nervous system circuits in order to treat patients with seizures, motor and sensory problems, and chronic pain.
Chief Scientific Founder and Co-Founder Dr. Shane Hegarty, PhD, says, “We are grateful to the SynGAP Research Fund for providing access to critical resources for performing key proof-of-concept studies on our KCC2-potentiating therapies in patient-derived neuron and glia models of SYNGAP1 syndrome. SRF has built an important platform which enables high-impact research and collaborations, which I hope will facilitate new treatments for SYNGAP1 patients.”
Principal Investigator, Dr. Shilpa Kadam, PhD, commented “This is a unique collaboration between academia/biotech, bringing researchers with a common goal to help drive early and safe interventional trials for the SYNGAP1 patient community using promising small molecule drugs. The clinical impact for this investigation is promising. Given the validated potential of KCC2 modulation in correcting E/I balance in neurons, we are excited for the support and opportunity to deliver new therapies to this patient community.”
SYNGAP1-related intellectual disability (ICD-10 F78.A1) is a rare genetic disorder caused by variants on the SYNGAP1 gene that reduce SynGAP protein levels. This protein acts as a regulator in the synapses (where neurons communicate with each other). When SynGAP protein levels are too low, we see an increase in excitability in the synapses making it difficult for neurons to communicate effectively. This leads to many neurological issues seen in SynGAP patients.
Symptoms of SYNGAP1 include: intellectual disability; epilepsy; hypotonia (low muscle tone); gross and fine motor skill delays; autism spectrum disorder; gastro-intestinal disorders; sleep and behavior disorders and visual abnormalities.
About AXONIS Therapeutics
AXONIS Therapeutics, Inc. is a biotechnology company based in Cambridge, MA, committed to advancing breakthrough drug discoveries to develop first-in-class therapies for currently incurable neurological disorders. AXONIS Therapeutics is progressing a pipeline of neuron-reviving therapeutics which enable an intrinsic ability of central nervous system (CNS) neurons to resist degeneration; restore excitation/inhibition balance; and regenerate, with the goal of making a real difference for patients, their families and the global healthcare system. For more information, visit https://axonis.us/.
About the Tang Lab
The Tang Lab at Boston Children’s Hospital is dedicated to drug discovery for treating brain diseases. The lab studies the molecular, cellular, and neural-network basis of human brain diseases to ultimately develop precision medicine therapeutics. With a focus on neurodevelopmental disorders, epilepsy, and brain tumors, researchers in the Tang lab develop innovative small molecule, nucleic acid, and cell therapeutic strategies to treat or even cure such devastating brain diseases.
About the SynGAP Research Fund
The mission of the SynGAP Research Fund is to improve the quality of life for SYNGAP1 patients through the research and development of treatments, therapies and support systems. SRF was founded in the US in 2018 as a 501(c)(3) US public charity, and families created sister organizations for SRF in the UK in 2020, in Europe (Netherlands) in 2022 and in Latin America (Colombia) in 2023. Completely parent-led, SRF is the largest non-government funder of SynGAP research having committed over $3.5 million in grants to date. The founders cover all operational costs, ensuring donations fund progress, not foundation overhead. SRF’s grant program awards one or two-year grants to young investigators, physician residents, and clinicians who are interested in studying SYNGAP1. SRF grants are intended to help researchers explore novel ideas and answer questions related to the clinical aspects, therapies and/or genetic causes of SYNGAP1. SRF is a member of the COMBINEDbrain, Global Genes Foundation Alliance, the Everylife Foundation Community Congress, Personalized Medicine Coalition, Rare Epilepsy Network, and Epilepsy Leadership Council.
For more on SRF, visit: SyngapResearchFund.org or follow @cureSYNGAP1