Adrenoceptors Antagonists for the Prevention and Treatment of Neurodegenerative Conditions

Tech ID: tag000709

 

Introduction

This invention discloses a new strategy to treat Idiopathic Parkinson’s Disease (iPD) at the stage that precedes the motor symptom state, known as “pre-motor symptom” stage, using adrenoceptor antagonists such as carvedilol. Also included is a non-invasive method to diagnose iPD and monitor its progression, which allows treatment before iPD enters the motor symptom state. Otherwise, these patients could miss the window of opportunity for treatment. Accordingly, this treatment strategy can slow down iPD progression or reduce the likelihood of progression to iPD with motor symptoms. 

 

Technology Description

Idiopathic Parkinson’s Disease (iPD) is a non-hereditary, chronic, and progressive neurodegenerative disorder associated with a significant loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). No existing treatment can slow down or stop disease progression, and the symptomatic treatment based on dopaminergic supplementation can only temporarily improve motor impairment. Motor symptoms do not occur until 50-80% of the dopaminergic neurons are lost. However, several frequent clinical features of iPD can’t be explained by the dopaminergic neuron degeneration theory. Notably, many non-motor symptoms such as constipation do not respond to dopaminergic supplementation yet precede motor symptoms by years. In addition, protein aggregates (Lewy bodies) rich in α-synuclein and ubiquitin, the pathological marker of iPD, are also found in autonomic and noradrenergic structures which are involved in iPD progression.

 

Dr. Tagliati and Dr. Pagano concluded that dysfunction of noradrenergic system can explain many of these early non-motor symptoms and iPD progression. In this model, the excessive activation of the noradrenergic system increases levels/activities of G-coupled receptor kinases which causes abnormal phosphorylation and aggregation of α-synuclein. Therefore, blocking adrenergic receptors can potentially reduce/revert the pathological mechanism leading to α-synuclein aggregation, which will ultimately decrease neuronal death and slow disease progression. This model is supported by clinical evidence, such as beta-blockers that significantly reduced constipation in iPD patients.

 

Furthermore, this invention includes measuring cardiac uptake of iodine-123-metaiodobenzylguanidine (123I-MIBG), an analog of norepinephrine, to diagnose subjects suspected of having iPD and monitoring disease progression. Decreased cardiac intake of 123I-MIBG has been reported in iPD patients, and the mechanism has also been linked to the noradrenergic system dysfunction. Together, these new strategies allow the diagnosis and treatment of iPD at the “pre-motor symptoms” stage, where patients are not diagnosed with iPD (see Langston et al., 2018).

 

Final approval is pending for a clinical trial focusing on early diagnosis and intervention of iPD.

 

Applications

•       These findings can lead to the development and repurpose of adrenoceptor blockers to treat iPD at pre-motor symptom stage and prevent its progression.

 

Intellectual Property

Patent applications filed in US, EU, Japan, and South Korea. Claims are directed towards treatment and diagnosis methods. [Link]

US patent 10,111,879 granted

 

Selected Publication

Pagano et al. Constipation is reduced by beta-blockers and increased by dopaminergic medications in Parkinson's disease. Parkinsonism& Related Disorders. 2015, 21: 120-125 [Link]

Langston et al. Optimizing diagnostic in Parkinson’s disease: The Role of A dual imaging algorithm. Nature Parkinson’s disease 2018 [Link]

 

 

 

For more information, please contact Cedars-Sinai Technology Transfer Office:

 

Wenyue Du, PhD

Senior Licensing Associate - IP Portfolio Management & Licensing

T: +1 310-423-2241

E-mail: wenyue.du@cshs.org

 

Song Qu, PhD

Licensing Associate – IP Portfolio Management & Licensing

T: +1 310-423-6460

E-mail: song.qu@cshs.org

 

Patent Information:
For Information, Contact:
Wenyue Du
Senior Associate - IP Management & Licensing
310-423-2241
wenyue.du@cshs.org
Inventors:
Michele Tagliati
Gennaro Pagano
Keywords:
Neurosciences