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
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.
Available from: Taher Darreh-Shori
- "Den aktiva delen är kopplad till den tunna plastkatetern (tether). En förstoring av den aktiva delen i bildens högra del visar de NGF-producerande cellerna innanför den halvgenomsläppliga membranväggen, som möjliggör inflöde av näringsämnen och syre samt utflöde av NGF (modifierad från Wahlberg et al 2012). hjärnan under lång tid, och har också fördelen att de inkapslade cellerna lätt kan tas bort vid behov. "
Available from: Terry C Burns
- "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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ABSTRACT: Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer׳s disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man.
Copyright © 2015. Published by Elsevier B.V.
Available from: Taher Darreh-Shori
- "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)  . This study was conducted according to the Declaration of Helsinki and subsequent revisions. "
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ABSTRACT: Background: Extensive loss of central cholinergic functions in AD brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF).Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. Hypothesis: EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT and acetylcholinesteraseResult: Activities of both enzymes were altered after 12 months. In particular, activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-β, in vivo cerebral glucose utilization and nicotinic binding sites, as well as morphometric and volumetric MRI measures.Conclusion: A clear pattern of associations is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy
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