Beclin 2-Functionalized Therapies for Treatment of Neurodegenerative Disease and Cancer

 

This invention identified that Beclin 2 functions as a negative regulator of the ERK1/2 signaling, NF-κB signaling, and inflammasome activation. Furthermore, these studies demonstrated that Beclin 2 targets key signalling kinases for degradation through an ATG9A-dependent autophagic pathway. These new findings have uncovered an important role of Beclin 2 in the prevention and treatment of inflammatory diseases, neurodegenerative diseases, and tumor development, thus providing a new potential therapeutic target for these diseases. Therapeutic strategies including the direct manipulation of Beclin 2 and the development of Beclin 2-scFv fusion proteins and Beclin 2-small molecule drug complexes are currently underway.

 

Stage of Development

 

In vitro data: In depth mechanistic studies revealed that Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Additionally, in cell-based assays, Beclin 2 was able to induce degradation of neurodegenerative-related proteins such as Tau in a dose-dependent manner. 

In vivo data: In cancer applications, Beclin 2-deficient mice displayed an increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 completely rescued the phenotypes of these mice.

 

Competitive Landscape

 

Prior to these studies, Beclin 2 was known to play a critical role in metabolic regulation and obesity, but its functions in innate immune signaling, neurodegenerative disease, and cancer development were largely unknown. Many of the current treatments for cancer or neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are either highly toxic or ineffective. As such, the search for effective drugs is being actively pursued worldwide. This invention addresses these lissues by identifiying a new therapeutic target, Beclin 2, and developing novel strategies to modulate Beclin 2 as a method of treating neurodegenerative diseases and/or cancer. 

 

Competitive Advantages

 

•       Potential for first-in-class designation

 

Patent Information:
Licensing Contact
Paige Glumac
pglumac@houstonmethodist.org

Inventors:
Rongfu Wang
Helen (Yicheng) Wang
Motao Zhu