Parkinson’s disease is one the most frequent neurodegenerative disorders affecting a progressively larger population worldwide. The exact initial pathophysiology leading to a profound cellular dysfunction of dopamine secreting neurons in the midbrain and cellular accumulation of metabolic byproducts leading to death remains unknown. The early stages respond usually well to medical management, consisting mainly of oral ingestion of precursors of dopamine, or dopamine receptors agonists or metabolite antagonists. But the progression of the disease is irreversible and lead to more advanced stages with debilitating motor and non-motor symptomatology. Chronic medical therapy causes secondary complications, sometimes worse than the disease itself. Surgical procedures such as the implantation of chronic stimulators within different targets can lead to symptomatic improvement in the motor functions. This improvement is usually transient but may benefit some patients for several years. Other symptoms progress however with increasing oral intake of dopaminergic medication and stimulation parameters.
Parkinson’s disease is a relatively confined pathological disorder within the basal ganglia, at least initially. Cellular replacement therapy (CRT) appears applicable to this disorder and has been investigated at the basic and clinical level for several years. Most of the studies assumed a simple deficit of focal dopaminergic discharge, and used a classic animal.
Our current translational effort gives us a unique position in CRT. It is based on the selective isolation, expansion and differentiation of autologous adult neural stem cells with epigenetic factors, replicating certain steps of human neurogenesis by inducing a shift in the expression pattern of homeobox genes in vitro. Unlike embryonic stem cells, adult neural stem cells have a committed path to the formation of tissue from the central nervous system, and the unique autologous approach makes this therapy immune-compatible with minimal infectious risks.
Our objectives in this proposal aims at achieving the planning for the following activities to be funded under Part II:
a)To create a CIRM Parkinson’s Disease Therapy Team linking academic scientists, animal model experts, clinical trials experts, and regulatory specialists to prepare a new IND filing with the FDA.
b)To establish a cGMP manufacturing facility and complete Production, Storage and Process Controls for clinical grade Target Product validation.
c)To complete parallel IND enabling animals studies with new animal models of PD.
d)To lay the foundation for a Phase I/II prospective randomized control surgical trial to be completed within 4 years of funding.
Statement of Benefit to California:
This proposal meets several goals from the CIRM 2009 syllabus on its mission and roles within the State of California. [REDACTED], will establish its animal studies in [REDACTED] and establish a cGMP facility within the state as well. The clinical trial will be conducted in [REDACTED]. It will be one of the first clinical study using autologous adult neural stem cells for advanced Parkinson's disease. A multidisciplinary team of clinicians and scientists will be fully committed for the duration of the funding to seek a potential revolutionary treatment for Parkinson's disease.
Our group will develop collaborative networks with world renowned experts in the field of neurodegenerative disorders and those scientists already funded by CIRM and working both at the basic and preclinical levels. Experts in clinical surgical trials, statisticians, ethicists, neurologists will oversee the proposed Phase II trial once approved by the FDA.