Phase I Cell Therapy for Maintaining Cholinergic Circuits in the Spectrum of Alzheimer's Disease

PROJECT SUMMARY/ABSTRACT Cognitive decline in the spectrum of Alzheimer’s disease (AD) including Lewy Body Dementia (LBD) and Parkinson’s disease with dementia (PDD) takes a severe toll on patients, family, and society in suffering and cost. The memory and cognitive deficits observed in AD, LBD and PDD are attributable in large part to a loss of cholinergic function and neurons in the brain, especially in the nucleus basalis of Meynert (NBM). The greatest unmet need for AD, LBD and PDD are therapies that can go beyond symptom treatment to possibly stabilize or maintain cholinergic circuits. As part of clinical trials, we have been delivering mixed-cell, pro-regenerative peripheral nerve tissue (PNT) to areas of the brain affected in neurodegenerative disease. Here we propose a Phase I single surgical-center, double-blinded clinical trial involving bilateral autologous PNT into the NBM to address “repair cell” support of cholinergic neurons. The major goal of this trial is to identify the feasibility and safety of bilateral implantation of reparative PNT to the NBM with the eventual goal to improve function of cholinergic neurons in dementias. Twenty-four participants, diagnosed with PD and who have selected, qualified, and agreed to undergo DBS surgery of the globus pallidus internus (GPi), will be followed for 24 months as part of a trial to receive, at the time of DBS surgery, PNT implanted bilaterally into the NBM (twelve participants) or an alternate target also affecting cognition in this population, the substantia nigra (SN). DBS will be implanted and programmed to provide the standard of care. Feasibility objectives will be based on the number of participants receiving PNT delivery and the number of participants completing the 24-month study visit. For the safety objective, the number of serious adverse events related to the procedure will be collected for 24 months following surgery. Cognitive safety endpoints at 12 and 24-months following surgery will be defined as ≥ 1.5 standard deviation decrement relative to the participant’s estimated pre-morbid functioning. To aid in future trial designs, secondary endpoint analyses will use extensive neuropsychology testing of subjects, Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) evaluations, and quality of life assessments at 6, 12 and 24 months after surgery compared to baseline. We will continue to expand our brain bank activities in conjunction with the University of Colorado Health Science Center to assess the histological effects of the investigational cell therapy in participants who donate their brain after death. This study is a critical step for identifying the feasibility of this NBM vs. SN design for trialing in subsequent multicenter, Phase II studies and for continuing to move this approach forward as an eventual monotherapy for the treatment of the Spectrum of AD.