RESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Doença de Alzheimer/terapia , Dependovirus/genética , Terapia Genética/métodos , Fator de Crescimento Neural/genética , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Núcleo Basal de Meynert , Estudos de Viabilidade , Feminino , Vetores Genéticos , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Procedimentos Neurocirúrgicos , Tomografia por Emissão de Pósitrons , Técnicas Estereotáxicas , Resultado do TratamentoRESUMO
PURPOSE: To develop CERE-120 (AAV-NTN) as a novel therapy for Parkinson's disease (PD) that might restore function of degenerating dopamine neurons and prevent further degeneration. SCOPE: A nonclinical program demonstrated that NTN expression can be predictably controlled following CERE-120 administration, provides clear evidence of efficacy in numerous animal models and is safe at dose multiples that far exceed those required for efficacy. Preliminary, open label evidence in PD subjects offers corroborative support for these observations. CONCLUSIONS: CERE-120 may represent an important, novel therapy for PD, though the clinical data require confirmation with additional clinical tests, including an ongoing multi-center, double-blinded controlled trial.
Assuntos
Terapia Genética/métodos , Neurturina/fisiologia , Doença de Parkinson/terapia , Animais , Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Humanos , Neuropeptídeos , Neurturina/genéticaRESUMO
Neurotrophic factors have long shown promise as potential therapies for age-related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE-120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long-term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof-of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol-prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational research and development for age-related and other neurodegenerative diseases.