Generation of mature neurons differentiated from differentiated stem cells by manipulating RNA splicing

This technology is a method for accelerating the maturation of neurons derived from pluripotent stem cells by controlling the expression of RNA splicing factors, particularly Muscleblind Like Splicing Regulator 2 (Mbnl2), enabling better modeling of late-onset neurodegenerative diseases.

Unmet Need: Stem cell models achieving neuronal maturity for disease studies

Current experimental models of neurodegenerative diseases rely heavily on immature neuronal cultures derived from induced pluripotent stem cells (iPSCs), which fail to reach adult-like maturity in a dish. This limitation significantly hampers the ability to study age-related neurological disorders, as these immature neurons do not accurately represent the cellular environment where diseases typically manifest. While iPSC technologies have revolutionized disease modeling, the field lacks reliable methods to generate mature neurons that can effectively model late-onset conditions.

The Technology: RNA splicing-based approach for accelerating neuronal maturation

This technology is a method for generating mature neurons from differentiated stem cells by harnessing the power of alternative splicing regulation. It drives neuronal maturation by overexpressing Mbnl2, a master regulator of developmental alternative splicing programs. The approach involves controlled expression of Mbnl2 in iPSC-derived neurons to accelerate their maturation process and achieve adult-like splicing patterns. This method produces neurons that better reflect the mature state needed for studying age-related diseases.

The technology has been validated through initial experiments demonstrating successful viral induction of Mbnl2 expression in cell lines and its effects on neuronal maturation patterns.

Applications:

• Development of improved disease models for neurodegenerative disorders
• Drug screening and therapeutic development platform
• Study of age-related neurological conditions
• Research tool for investigating neuronal maturation mechanisms
• Generation of mature neurons for cell-based therapies
• Investigation of RNA splicing dynamics in neuronal development
• Platform for studying patient-specific disease mechanisms using iPSCs

Advantages:

• Accelerates neuronal maturation compared to conventional methods
• Generates neurons that better represent adult cellular states
• Compatible with existing iPSC protocols and platforms
• Enables more physiologically relevant disease modeling
• Provides controlled manipulation of maturation processes
• Can be applied to patient-derived cells for personalized medicine

Lead Inventor:

Chaolin Zhang, Ph.D.

Patent Information:

Patent Pending (WO/2024/249893)

Related Publications:

• Valadez-Barba V, Cota-Coronado A, Hernández-Pérez OR, Lugo-Fabres PH, Padilla-Camberos E, Díaz NF, Díaz-Martínez NE. “iPSC for modeling neurodegenerative disorders.” Regen Ther. 2020 Dec; 15: pp 332-39.

• Weyn-Vanhentenryck SM, Feng H, Ustianenko D, Duffié R, Yan Q, Jacko M, Martinez JC, Goodwin M, Zhang X, Hengst U, Lomvardas S, Swanson MS, Zhang C. “Precise temporal regulation of alternative splicing during neural development.” Nat Commun. 2018 Jun; 9(1): p. 2189.

• Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti MM, Zia G, Kumar A, Ashizawa T, Clark HB, Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Gomes-Pereira M, Gourdon G, Sakai N, Nishino S, Foster TC, Ares Jr M, Darnell RB, Swanson MS. “Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy.” Neuron. 2012 Aug; 75(3): pp. 437-50.

Tech Ventures Reference:

• IR CU24262

• Licensing Contact: Joan Martinez