Directed Differentiation of ES Cells to Neurospecific Lineages for Therapeutic and Research Use

Summary of Invention

Enlarge Image Currently, there are no curative therapies for Parkinson's disease or other diseases associated with loss of dopaminergic neurons (mDA).  Administration of L-Dopa, the current standard of care, is not curative and is associated with substantial side effects.  Various methods to drive directed differentiation of mDA-like neurons from human embryonic stem (hES) or induced pluripotent stem (iPS) cell sources exist, but the resulting mDA-like neurons show poor engraftment and poor long-term survival.  In addition, transplant of these mDA-like neurons often causes teratoma formation, and they are, therefore, not suitable for therapeutic use.  There is an unmet need for improved cell therapies for the treatment of Parkinson’s disease and other diseases associated with the loss of mDA neurons.   

Dr. Lorenz Studer and colleagues have perfected a method for the directed differentiation of mDA neurons from hES or iPS cells for therapeutic and research use.  This novel protocol is based on the use of small molecules to drive differentiation of mDA neurons from a floor-plate intermediate; floor-plate intermediates are generated through dual smad inhibition using LDN-193189 (BMP Inhibitor) and SB431542 (ALK Inhibitor).  To direct the selective differentiation of mDA neurons, activators of SHH, FGF8, and Wnt (recombinant SHH or purmorphamine, FGF8, and CHIR99021, respectively) are added in a temporal fashion, resulting in production of mDA neurons marked by expression of FOXA2/LMX1A/TH1 within 25 days of protocol initiation.  These functional neurons produce dopamine and fire with an electrophysiological profile that mimics endogenous mDA neurons.  In vivo transplantation of these mDA neurons results in long-term stably engrafted functional neurons with no evidence of teratoma formation.  Dr. Studer and colleagues have shown that engraftment of these mDA neurons in mouse, rat, and primate models of Parkinson's disease ameliorates symptoms and offers the potential for long-term curative treatment.

In addition, these mDA neurons are a useful disease modeling tool to study Parkinson’s disease or other diseases associated with loss of mDA neurons.

Advantages

• Long-term functional in vivo engraftment provides possible curative treatment;
• Accelerated differentiation timeline and scalability of method supports commercial utility;
• Lack of teratoma formation or neural overgrowth indicates increased safety over other methods of differentiation;
• Ability to use iPS or hES as source material allows flexibility in production, circumventing potential regulatory or legal hurdles

Areas of Application

• Adoptive cell therapy for the treatment of Parkinson’s and other diseases mediated by the loss of dopaminergic neurons;
• Research tool for disease modeling and drug screening

Stage of Development

• Pre-clinical proof-of-concept established in mouse, rat, and primate models of Parkinson’s disease;
• IND-enabling studies initiated

Lead Inventor

Lorenz Studer, MD

Publication

• Kriks, S. et al. (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.  Nature 480:547-51.
• Osherovich, Lev (2011) Stem cell jackpot for Parkinson’s disease. SciBX 4:8-9.

Intellectual Property Status

U.S. provisional application filed

Contact Information

Imke Ehlers, PhD, CLP
Licensing Manager
ehlersi@mskcc.org
Tel: 646-888-0580; Fax: 212-717-3439