Ovid research is pioneering a scientific approach to develop therapies based on new understanding of key biological pathways and their central role in rare neurological diseases.
We seek to develop medicines using novel and clinically relevant endpoints to capture tangible patient benefits that emanate from addressing underlying disease pathology.
While these rare neurological disorders are each caused by distinct genetic mutations in the brain, they result in similar impairments and symptoms – seizures, developmental and learning delays, sleep disturbances, and movement and behavioral issues. Because of the similar features and symptoms expressed in these disorders, we believe the medicines we are developing may have broad potential application across a number of rare neurological diseases.
Our initial focus is on treating Angelman syndrome and Fragile X syndrome, two disorders that fall on the Autism spectrum and are caused by genetic mutations. In Angelman syndrome, the mutation is most commonly a microdeletion on chromosome 15 encompassing the UBE3A gene. In contrast, in Fragile X syndrome there is an increase in the number of triplet repeats in the FMR1 gene, located on the X chromosome.
Developing BoldMedicine to Transform the Lives of People with Rare Neurological Diseases
“The cause is hidden.
The effect is visible to all.”
– Ovid, Metamorphoses
Rare Diseases of the Brain
About Angelman Syndrome
Angelman syndrome is a rare, genetic disorder that causes developmental disabilities and neurologic problems, such as difficulty speaking, balancing and walking, as well as other symptoms such as anxiety, sleep disturbances and seizures. The most common, genetic cause is a deletion of the Ubiquitin protein ligase E3A (UBE3A) gene located on chromosome 15. The first signs of Angelman syndrome are usually developmental delays, such as lack of crawling or walking, seen between the ages of 6 and 12 months. Due to its similarity to other disorders, misdiagnosis is frequent.
About Fragile X Syndrome
Fragile X syndrome (FXS) is thought to be the most common inherited form of intellectual disability with an estimated prevalence of 1 in 4,000 males and 1 in 8,000 females. It is considered to be the most common known genetic cause of autism, with approximately 25-30 percent of children with FXS meeting the full diagnostic criteria for autism, and approximately 5 percent of children with autism carrying the Fragile X mutation. The cause of FXS is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in the lack of fragile X mental retardation protein expression which is required for normal development.
Intellectual disability and behavioral problems are common in males diagnosed with FXS. Males with FXS have moderate-to-severe intellectual disability and females range from normal to moderate impairment. Individuals with FXS are at increased risk for a range of co-occurring behavioral problems that may cause limitations in their academic, adaptive, daily living function and social interactions. The most common behavioral issues include attention problems, hyperactivity, anxiety, aggression, poor sleep and self-injury.
Targeting Tonic Inhibition
Angelman syndrome and Fragile X syndrome are both rare neurogenetic conditions associated with developmental delays, physical characteristics and behavioral challenges.
It is believed that the symptoms of Angelman syndrome and Fragile X syndrome are a result of disrupted tonic inhibition.
What is Tonic Inhibition?
Tonic inhibition is what allows a healthy human brain to decipher signals correctly without being overloaded. A human brain is being constantly inundated with sensory information – sights, smells, sounds and touch – and tonic inhibition is what allows the brain to filter out the “white noise” and focus on the important information. If tonic inhibition is reduced, the brain becomes inundated with signals and loses the ability to separate background noise from critical information.
Tonic inhibition is key to the brain's ability to discriminate signal from noise.
GABA is a Key Player in Tonic Inhibition
The brain is composed of a vast network of interconnected neurons that facilitate the communication between cells. These communications are governed by the release of chemical signals, or neurotransmitters, across the synaptic gap (the physical gap separating two neurons). Neurotransmitters can create an excitatory signal – which carry messages that tell us how to move and speak – and inhibitory signals – which regulate how well, or not, we’re able to receive those signals. GABA is the primary inhibitory neurotransmitter in the human brain.
GABA signaling is involved in critical functions, like motor control, sleep, behavior and cognition. Under normal conditions there is sufficient GABA present to stimulate synaptic and extrasynpatic (outside the synaptic gap) GABAA receptors. But in Angelman syndrome and Fragile X syndrome, the overall levels of GABA are reduced. This can lead to a situation in which there is not enough or insufficient GABA outside the synapse to stimulate the extrasynaptic receptors and maintain longer-term, or tonic, signaling. The decline in tonic inhibition triggered by the shortage of GABA leads to the chronic activation of the neurons receiving the signal and disruption of normal brain network activity.
In Angelman syndrome, there is a ubiquitin-protein ligase E3A (UBE3A) genetic defect that disrupts the cell’s normal maintenance function of tagging proteins for degradation. As a result, the GABA transport 1 (GAT1) protein is not tagged for degradation. The GAT1 protein is responsible for the reabsorption of GABA from the synaptic terminal into the presynaptic neuron. When not tagged for degradation, reabsorption of GABA into the presynaptic neuron continues, and GABA levels decrease in the synaptic terminal. This then leads to a loss of tonic inhibition.
In Fragile X syndrome, the fragile x mental retardation 1 (FMR1) genetic defect leads to a reduction of expression of the glutamate decarboxylase 65/67 (GAD 65/67) enzyme. This enzyme is responsible for the synthesis of GABA. In this syndrome, there is a reduced level of production of GABA within the presynaptic neuron. Hence, it is thought that there is a lower level of GABA available for release into the synaptic terminal which leads to a loss of tonic inhibition.
The relationship between neural signaling and Angelman syndrome and Fragile X syndrome.
We believe our lead program, OV101 (gaboxadol), is the only clinically tested δ-selective direct-acting GABAA receptor agonist. This means it is able to bind to and activate this specific δ-subset of GABA receptors, which are found in the extrasynaptic space outside of the synapse. There are many types of GABA receptors in the brain, which help regulate neuronal activity, but tonic inhibition is specifically a function of the δ-subunit containing GABAA receptors.
In Angelman syndrome and Fragile X syndrome, tonic inhibition is diminished; with OV101, we aim to restore that function. By signaling through the δ-selective GABAA receptor, OV101 can potentially make up for the loss of tonic inhibition, which we hope will relieve several of the symptoms of these disorders. In preclinical animal models, OV101 improved symptoms of Angelman syndrome and Fragile X syndrome, such as motor function, sleep and aspects of behavior and cognition.
Gaboxadol was originally being developed for sleep disorders and was acquired by Ovid from H. Lundbeck A/S in 2015.
1 J Neurosci. 2008 Feb 6;28(6):1421-6. doi: 10.1523/JNEUROSCI.4751-07.2008.
Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? Glykys J1, Mann EO, Mody I.
In working with foundations focused on Angelman syndrome, we have designed a double-blind, placebo-controlled, randomized Phase 2 clinical trial, named STARS, looking at safety parameters and exploratory efficacy endpoints in adults with Angelman syndrome. We plan to begin enrolling patients soon.
We called on the Angelman syndrome community to help us design the clinical trial, including identifying the trial endpoints. They also selected the final STARS clinical trial name and logo. The STARS logo was designed by Kaline, a proud parent of a child diagnosed with Angelman syndrome. The image “reaching for the STARS” is a depiction of her son, and every other person diagnosed with Angelman syndrome, standing with one foot firmly planted while using the “T” to stretch as far as they can to reach the brightest star in the sky.
Learn more about our STARS trial from our chief medical & portfolio management officer, Dr. Amit Rakhit, as he speaks with the Angelman Syndrome Foundation and the Foundation for Angelman Syndrome Therapeutics.
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