Development of a Drug that Strengthens Synaptic Connections for the Potential Treatment of Angelman Syndrome: The Role of BDNF

Quick Overview

Dr. Marshall discusses the development of drugs that strengthen synaptic connections for the potential treatment of Angelman Syndrome. These drugs aim to increase the activity of brain-derived neurotrophic factor (BDNF), a growth factor important for synaptic plasticity. In Angelman Syndrome, synapses appear weaker due to deficits in BDNF signaling. Dr. Marshall’s team has developed a compound called Syn3 that disrupts the interaction between a protein called Arc and PSD-95, allowing BDNF to activate signaling pathways. The compound has been shown to cross the blood-brain barrier and restore normal signaling in human neurons. In animal models, the drugs have been found to increase levels of synaptic proteins, induce long-term potentiation (LTP), and improve learning and memory. They have also shown promise in reducing seizure activity and improving motor performance. The drugs could potentially be administered subcutaneously, intranasally, or orally. The research has been funded by FAST.

Introduction

In this talk, we will discuss the development of drugs that aim to strengthen synaptic connections for the potential treatment of Angelman Syndrome. Specifically, we will focus on the role of brain-derived neurotrophic factor (BDNF) in this process. Angelman Syndrome is a neurodevelopmental disorder characterized by weak synapses and deficits in BDNF signaling.

Understanding Synaptic Connections and BDNF

Synaptic connections are the points where nerve cells interact, allowing for the transmission of electrical impulses. These connections play a crucial role in various functions such as learning, memory, speech, and motor skills. BDNF is a growth factor that is essential for the strengthening of synaptic plasticity, which refers to the ability of neurons to change their strength.

Deficits in BDNF Signaling in Angelman Syndrome

In individuals with Angelman Syndrome, the synapses appear to be weaker and do not strengthen properly. This is believed to be due to deficits in BDNF signaling. When BDNF binds to its receptor, it activates various signaling pathways, including the PI3K kinase enzyme and mTOR. These pathways are crucial for the expression of proteins and receptors that strengthen synapses.

Developing a Drug to Enhance BDNF Signaling

To address the deficits in BDNF signaling, researchers have developed a compound called Syn3. This compound binds to a protein called PSD-95, which is abundant at synapses. In Angelman Syndrome, the absence of UBE3A leads to increased levels of a protein called Arc, which interferes with the ability of PSD-95 to signal. Syn3 disrupts the interaction between Arc and PSD-95, allowing BDNF to activate the signaling pathway and strengthen synapses.

The Efficacy of Syn3

Syn3 has been found to have high affinity for PSD-95 and is designed to bind to two different sites, increasing its specificity for the protein. Additionally, researchers have developed a more stable version of Syn3 called D-Syn3, which has shown promising results in animal studies. Both Syn3 and D-Syn3 have been shown to cross the blood-brain barrier and maintain high concentrations in the brain for several hours.

Administration of the Drug

The drugs can be administered through various methods, including subcutaneous injection, intranasal delivery, and potentially oral administration. These different routes of administration offer flexibility and ease of use for potential patients.

Restoring BDNF Signaling and Synaptic Proteins

Experiments using human neurons have shown that the drugs effectively restore BDNF signaling, as indicated by the activation of proteins in the signaling pathway. In animal models of Angelman Syndrome, the drugs have been found to increase the levels of synaptic proteins that are important for the formation and release of neurotransmitters. This restoration of synaptic proteins is crucial for synaptic strength and plasticity.

Long-Term Potentiation and Behavioral Effects

Long-term potentiation (LTP) is a molecular process associated with learning and memory. In Angelman mice, LTP is impaired, but the administration of Syn3 and D-Syn3 has been shown to restore LTP. Furthermore, these drugs have demonstrated positive effects on seizure susceptibility, learning, and motor coordination in animal models of Angelman Syndrome.

Future Directions and Acknowledgements

The researchers involved in this study are working towards developing an oral formulation of the drugs for easier administration. The results obtained so far have been made possible through funding from the Foundation for Angelman Syndrome Therapeutics (FAST). The researchers express their gratitude to the parents and fundraisers who have supported their work.

In conclusion, the development of drugs that enhance synaptic connections and restore BDNF signaling shows promise for the potential treatment of Angelman Syndrome. These drugs have demonstrated positive effects on synaptic proteins, long-term potentiation, and various behavioral aspects in animal models. Further research and development are needed to advance these drugs towards clinical trials and potential use in patients with Angelman Syndrome.