Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Neurosurgery, University Hospital, Stockholm, Sweden. luw@nsgene.com
Lars U
LU
Wahlberg
Göran
G
Lind
Per M
PM
Almqvist
Philip
P
Kusk
Jens
J
Tornøe
Bengt
B
Juliusson
Michael
M
Söderman
Eva
E
Selldén
Åke
Å
Seiger
Maria
M
Eriksdotter-Jönhagen
Bengt
B
Linderoth
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000601:surgery*; D020532:Basal Nucleus of Meynert / Q000187:drug effects; D002214:Capsules; D002460:Cell Line; D002799:Cholinergic Fibers / Q000187:drug effects*; D015331:Cohort Studies; D020667:Diagonal Band of Broca / Q000187:drug effects; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004343:Drug Implants; D064420:Drug-Related Side Effects and Adverse Reactions; D004867:Equipment Design; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000008:administration & dosage*; D019635:Neurosurgical Procedures / Q000295:instrumentation* / Q000379:methods*; D011183:Postoperative Complications / Q000000981:diagnostic imaging; D016548:Prosencephalon / Q000187:drug effects*; D013238:Stereotaxic Techniques / Q000295:instrumentation; D053441:Suture Anchors; D014057:Tomography, X-Ray Computed
D002214:Capsules; D004343:Drug Implants; D020932:Nerve Growth Factor