Gene-based therapy of Parkinson’s Disease: Translation from animal model to human clinical trial employing convection enhanced delivery

Abstract

The existing treatment of Parkinson’s disease (PD) is directed towards substituting dopamine loss with either dopamine replacement therapy or pharmacological therapies aimed at increasing dopamine at the synapse level. Emerging viable alternatives include the use of cell-based and gene-based therapeutics. In this review, we discuss efforts in developing in vitro and in vivo models and their translation to human clinical trials for gene-based therapy of this distressing and prevalent neurodegenerative disorder. Given the mismatch between expectations from preclinical data and results of human pivotal trials, drug delivery has been identified as the key emerging area for translational research due to limitation of limited efficacy. The chief highlights of the current topic include use of improved delivery methods of gene-based therapeutic agents. Convection-enhanced delivery (CED), an advanced infusion technique with demonstrated utility in ex vivo and in vivo animal models has recently been adopted for PD gene-based therapy trials. Several preclinical studies suggest that magnetic resonance imaging (MRI)-guided navigation for accurately targeting and real time monitoring viral vector delivery (rCED) in future clinical trials involving detection of gene expression and restoration of dopaminergic function loss using pro-drug approach will greatly enhance these PD treatments.

Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue

“…Recent developments in the field of neuroprotective mediated therapeutic interventions using gene-based therapy to modify the progression of PD have been discussed in a comprehensive review. 13 The researchers are engaged in developing new strategies by employing emerging animal models of transgene viral vectors, target validation of CED with MRI, and testing efficacy of novel therapeutic agents using new designs of clinical trials. 27,28 …”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…CED-based in vitro, ex vivo and in vivo animal models have led to active genetherapy trials for treating Parkinson disease (PD)and are supported by histological studies on disease pathology [9].Use of MRI navigation in some clinical trials, helps accurately targeting and providing real time monitoring of viral vector delivery (rCED). Several researcher labs including ours adopted different small and large animal models exploring use of CED in brain [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The results from these studies are promising with a suggestion of superiority over intrathecal (IT) injection.…”

“…Commercially available systems for low volume, pressure monitored infusions may also be tested within the surrogate brain to determine infusion pump requirements for planned and future infusion protocols, including operating requirements such as MRI safety of the infusion system [11]. Findings during research on CED catheter design and development of CED stroke treatment lead to the merger of ultra-sound and CED.CED in regard to volume distributed (Vd), volume infused (Vi) and location using in vitro model, ex vivo brain animal models, in vivo insect, mouse, rat, and non-human primate models of PD have been reported in an effort to validate techniques for benchmarking infusion characteristics across models [9,10] and adopted for use in human gene-based therapy trials [10].…”

“…Could the injured spinal cord also have limited diffusion via CED similar to nerves, needs to confirm. Small silica cannula inserted in peripheral nerve; (10,20,30,40, and 80 ml) of 14C-labeled or gadolinium-labeled albumin were infused unilaterally or bilaterally into the tibial nerves of primates @ 0.5ml/min; and one primate infused bilaterally with gadoliniumbound albumin (40 ml/nerve) underwent MR imaging 16 weeks after infusion.…”

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

“…Convection-enhanced delivery (CED) has been proposed as a treatment option for a broad spectrum of neurological disorders including malignant brain tumors, epilepsy, metabolic disorders, neurodegenerative diseases (such as Parkinson disease) 1 , stroke, and trauma 2 . CED employs positive pressure bulk flow for the distribution of a drug or other infusate.…”