Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: A technology platform for restorative neurosurgery - Clinical article

Department of Neurosurgery, University Hospital, Stockholm, Sweden.
Journal of Neurosurgery (Impact Factor: 3.74). 06/2012; 117(2):340-7. DOI: 10.3171/2012.2.JNS11714
Source: PubMed


The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole.
Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), and after a safety evaluation, a second cohort of 3 patients received bilateral implants (a total of 4 implants per patient) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region). Stereotactic implantation of the devices was successfully accomplished in all patients. Despite extensive brain atrophy, all targets could be reached without traversing sulci, the insula, or lateral ventricles.
Postoperative CT scans allowed visualization of the barium-impregnated tethers, and fusion of the scans with stereotactic MR images scan was used to verify the intended positions of the implants. Follow-up MRI at 3 and 12 months postimplantation showed no evidence of inflammation or device displacement. At 12 months, implants were successfully retrieved, and low but persistent NGF secretion was detected in half of the patients.
With refinement, the ECB technology is positioned to become an important therapeutic platform in restorative neurosurgery and, in combination with other therapeutic factors, may be relevant for the treatment of a variety of neurological disorders. Clinical trial registration no.: NCT01163825.

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    • "In a small pilot clinical study, nerve growth factor(NGF)-overexpressing immortalized human pigment epithelial cells were stereotactically delivered to the basal forebrain in retrievable encapsulation devices (Wahlberg et al., 2012). This work followed from studies demonstrating robust long-term NGF delivery in Gottinberg minipigs (Fjord-Larsen et al., 2010), though lower survival of the encapsulated cells was seen after retrieval of the devices from human brains (Wahlberg et al., 2012). Preliminary clinical results demonstrated less brain shrinkage than expected based on historical MMSE-matched controls in a subset of patients (Ferreira et al., 2015), though results at this point should be considered very preliminary. "
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    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.041 · 2.53 Impact Factor
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    • "All patients were treated with cholinesterase inhibitors (ChEI) for a mean duration of 15 6 7 months at study start, and continued on the same dose throughout the study. Three patients received single EC-NGF implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (i.e., two implants per patient), and three patients received double bilateral implants (a total of four implants per patient ) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region) [15] [16]. This study was conducted according to the Declaration of Helsinki and subsequent revisions. "
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    • "In clinical trials, the CNTF secreting capsule has shown positive safety profile and stable production of the therapeutic protein for over 2 years [18] [19] [20]. Also the NGF producing cell capsule has shown promising results, but further refinement of the technology is needed [55]. For clinical suitability of this cell encapsulation system, the therapeutic protein is not expected to be a concern; the sVEGFR1 protein from human ARPE-19 cells should not cause immunological problems. "
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