Bartus, RT. Translating the therapeutic potential of neurotrophic factors to clinical ‘proof of concept’: a personal saga achieving a career-long quest. Neurobiol Dis 48: 153-178

Ceregene, Inc., San Diego, CA 92121, USA.
Neurobiology of Disease (Impact Factor: 5.08). 04/2012; 48(2):153-78. DOI: 10.1016/j.nbd.2012.04.004
Source: PubMed


While the therapeutic potential of neurotrophic factors has been well-recognized for over two decades, attempts to translate that potential to the clinic have been disappointing, largely due to significant delivery obstacles. Similarly, gene therapy (or gene transfer) emerged as a potentially powerful, new therapeutic approach nearly two decades ago and despite its promise, also suffered serious setbacks when applied to the human clinic. As advances continue to be made in both fields, ironically, they may now be poised to complement each other to produce a translational breakthrough. The accumulated data argue that gene transfer provides the 'enabling technology' that can solve the age-old delivery problems that have plagued the translation of neurotrophic factors as treatments for chronic central nervous system diseases. A leading translational program applying gene transfer to deliver a neurotrophic factor to rejuvenate and protect degenerating human neurons is CERE-120 (AAV2-NRTN). To date, over two dozen nonclinical studies and three clinical trials have been completed. A fourth (pivotal) clinical trial has completed all dosing and is currently evaluating safety and efficacy. In total, eighty Parkinson's disease (PD) subjects have thus far been dosed with CERE-120 (some 7 years ago), representing over 250 cumulative patient-years of exposure, with no serious safety issues identified. In a completed sham-surgery, double-blinded controlled trial, though the primary endpoint (the Unified Parkinson's Disease Rating Scale (UDPRS) motor off score measured at 12 months) did not show benefit from CERE-120, several important motor and quality of life measurements did, including the same UPDRS-motor-off score, pre-specified to also be measured at a longer, 18-month post-dosing time point. Importantly, not a single measurement favored the sham control group. This study therefore, provided important, well-controlled evidence establishing 'clinical proof of concept' for gene transfer to the CNS and the first controlled evidence for clinical benefit of a neurotrophic factor in a human neurodegenerative disease. This paper reviews the development of CERE-120, starting historically with the long-standing interest in the therapeutic potential of neurotrophic factors and continuing with selective accounts of past efforts to translate their potential to the clinic, eventually leading to the application of gene transfer and its role as the 'enabling technology'. Because of growing interest in translational R&D, including its practice in industry, the paper is uniquely oriented from the author's personal, quasi-autobiographic perspective and career-long experiences conducting translational research and development, with a focus on various translational neurotrophic factor programs spanning 30+ years in Big Pharma and development-stage biotech companies. It is hoped that by sharing these perspectives, practical insight and information might be provided to others also interested in translational R&D as well as neurotrophic factors and gene therapy, offering readers the opportunity to benefit from some of our successes, while possibly avoiding some of our missteps.

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Available from: Raymond T Bartus
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    • "Based on the history of the field to date, it seems clear that if protein-based therapeutics for the brain, including neurotrophic factors, are ever to provide consistent and meaningful benefit in the clinic, additional insight must be gained regarding the function and status of degenerating neurons in advanced human neurodegenerative diseases, including PD. This insight must include further understanding of how neurotrophic factors impact the status of degenerating human neurons, how the degeneration of these neurons, in turn, impacts the bioactivity of neurotrophic factors (Tuszynski et al., 2005; Love et al., 2005; Bartus et al., 2011; Rafii et al., 2014; Mittermeyer et al., 2012), and how the biology of these diseases in human brain may differ from those that exist in the animal models used to identify and test potential clinical candidates for testing in humans (Bartus et al., 2011, 2014). "
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    ABSTRACT: Substantial interest persists for developing neurotrophic factors to treat neurodegenerative diseases. At the same time, significant progress has been made in implementing gene therapy as a means to provide long-term expression of bioactive neurotrophic factors to targeted sites in the brain. Nonetheless, to date, no double-blind clinical trial has achieved positive results on its primary endpoint despite robust benefits achieved in animal models. A major issue with advancing the field is the paucity of information regarding the expression and effects of neurotrophic factors in human neurodegenerative brain, relative to the well-characterized responses in animal models. To help fill this information void, we examined post-mortem brain tissue from four patients with nigrostriatal degeneration who had participated in clinical trials testing gene delivery of neurturin to the putamen of patients. Each had died of unrelated causes ranging from 1.5-to-3-months (2 Parkinson's disease patients), to 4+-years (1 Parkinson's disease and 1 multiple-system atrophy-parkinsonian type patient) following gene therapy.
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    • "During the past decade, gene transfer has emerged as a practical means of overcoming all the obstacles associated with delivering recombinant neurotrophic factor protein to the brain, thus possibly providing the " enabling " technology required for translating the use of these proteins into viable biotherapeutics for human neurodegenerative diseases (for comprehensive reviews, see [33] [34]). Rather than attempting to deliver the large, three-dimensionally complex protein exogenously, the gene for the protein is delivered to the targeted site using a safe viral vector, thereby inducing local cells to manufacture and secrete the protein through their endogenous systems, potentially for the lifetime of the individual. "
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    ABSTRACT: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.
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    • "Moreover, of the ~50% subjects who remained blinded beyond the 12 months timeframe, a statistically significant effect was also seen on the primary endpoint, as well as even more secondary endpoints.37 Also, an exploratory statistical analysis indicated that the differences between AAV/NRTN and sham-surgery were highly unlikely to have occurred by chance (P < 0.007 and P < 0.001 at 12 and 18 months, respectively).5,41 "
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    ABSTRACT: Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path towards regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing CNS gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection, and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward - beyond our past limits.Molecular Therapy (2013); doi:10.1038/mt.2013.281.
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