AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: Long-term efficacy and tolerability of CERE-120 for Parkinson’s disease

  title={AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: Long-term efficacy and tolerability of CERE-120 for Parkinson’s disease},
  author={Mehdi Gasmi and Eugene Paul Brandon and Christopher D. Herzog and Alistair Z. Wilson and Kathie M. Bishop and Eva K. Hofer and Justine J. Cunningham and Marie A. Printz and Jeffrey H. Kordower and Raymond T. Bartus},
  journal={Neurobiology of Disease},

Transgene expression, bioactivity, and safety of CERE-120 (AAV2-neurturin) following delivery to the monkey striatum.

Estimation of the expression, bioactivity and safety of CERE-120, an adeno-associated virus type-2 (AAV2) vector encoding NTN, following delivery to the striatum of nonhuman primates provide substantial novel evidence for the potential utility of Cere-120 as a novel treatment for PD and support ongoing clinical trials testing CUE-120 in PD patients.


Evidence is provided of long-term expression and bioactivity of NTN on the dopaminergic nigrostriatal system after bilateral stereotactic delivery of CERE-120 to the striatum of nonhuman primates, and a wide safety margin is revealed.

Bioactivity of AAV2‐neurturin gene therapy (CERE‐120): Differences between Parkinson's disease and nonhuman primate brains

These data provide the first evidence that gene therapy can increase expression of a neurotrophic‐factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced, suggesting that serious axon‐transport deficits reduced the bioactivity of AAV2‐NRTN by limiting the protein exposed to the cell body.

Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys.

Clinical improvement and evidence of functional recovery in the nigrostriatal pathway, and the absence of adverse effects, support the safety of this approach for the delivery of GDNF over a 6-month period.

Gene therapy with AAV2-CDNF provides functional benefits in a rat model of Parkinson's disease

Treatment with AAV2‐CDNF resulted in a marked decrease in amphetamine‐induced ipsilateral rotations while it provided only partial protection of tyrosine hydroxylase (TH)‐immunoreactive cells in the rat substantia nigra pars compacta and TH‐reactive fibers in the striatum.

AAV2-neurturin (CERE-120) for Parkinson's disease

This review discusses early experiences with glial-derived neurotrophic factor in PD, the initial studies using AAV2-neurturin in PD patients, the lessons learned from these studies and the future directions of this therapy.



Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease.

It is found that the kinetics and pattern of NTN expression in the rat striatum following injection of CERE-120 is rapid, increases significantly up to 4 weeks, and exhibits a stable volume of distribution thereafter for at least 1 year, the longest time-point evaluated.

Striatal delivery of CERE‐120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys

Results are consistent with the neurotrophic effects of NTN on the dopaminergic nigrostriatal system and extend the growing body of evidence supporting the concept that AAV2‐NTN may have therapeutic benefit for Parkinson's disease.

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

Significant behavioral recovery was observed from 4–20 weeks following AAV-GDNFflag injection, indicating that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD.

Long-Term rAAV-Mediated Gene Transfer of GDNF in the Rat Parkinson's Model: Intrastriatal But Not Intranigral Transduction Promotes Functional Regeneration in the Lesioned Nigrostriatal System

The results demonstrate that both nigral and striatal transduction provide significant protection of nigral DA neurons against the toxin-induced degeneration, and provide evidence that rAAV is a highly efficient vector system for long-term expression of therapeutic proteins in the nigrostriatal system.

Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle

GDNF is highly effective as a neuroprotective and axon growth‐stimulating agent in the IS 6‐OHDA lesion model after both IS and ICV administration, and the lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.

Recombinant Adeno-associated Viral Vector-Mediated Glial Cell Line-Derived Neurotrophic Factor Gene Transfer Protects Nigral Dopamine Neurons after Onset of Progressive Degeneration in a Rat Model of Parkinson's Disease

Cell survival data indicate that a single delivery of rAAV encoding GDNF is efficacious when delivered after the onset of progressive degeneration in a rat model of PD and indicate that rAAVs-GDNF delivery results in a highly significant sparing of nigral DA neurons.

Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats.

Data indicate that the use of rAAV, a noncytopathic viral vector, can promote delivery of functional levels of GDNF in a degenerative model of Parkinson's disease.

Aberrant Sprouting and Downregulation of Tyrosine Hydroxylase in Lesioned Nigrostriatal Dopamine Neurons Induced by Long-Lasting Overexpression of Glial Cell Line Derived Neurotrophic Factor in the Striatum by Lentiviral Gene Transfer

The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired, which may be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum.

Short-Term GDNF Treatment Provides Long-Term Rescue of Lesioned Nigral Dopaminergic Neurons in a Rat Model of Parkinson’s Disease

It is concluded that not only preservation of the nigral DA neurons but also restoration of striatal DA function is necessary for functional recovery in the rat Parkinson model.