update news DDT Vol. 6, No. 1 January 2001

1359-6446/01/$ – see front matter ©2001 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(00)01621-46

Neurotech SA (Paris, France) andNSgene A/S (Copenhagen, Denmark)are developing an encapsulated celltechnology (ECT) for the delivery ofdrugs to the eye and the brain. The twoteams are currently working to developlong-lived cell lines that can be boundwithin a matrix-filled catheter deviceready for implantation for the treatmentof disorders such as age-related macu-lar degeneration, retinitis pigmentosa,Parkinson’s disease and epilepsy.

ECT is a potential solution to the prob-lems of delivering drugs and moleculesacross both the blood–eye and theblood–brain barrier. By introducing asmall, cell-containing semi-permeablecapsule directly into these two bodycompartments, ECT delivers secretedfactors to the required site. Furthermore,if problems arise during the treatmentphase, the small capsule, complete withcells, can be removed quickly.

Lessons from an early Phase IIb trialThe ECT technology was acquired byCytotherapeutics (Lincoln, RI, USA) inDecember 1999. Michael Lysaght (CEOat CytoTherapeutics and now Professorof Artificial Organs Research at BrownUniversity, Providence, RI, USA), carriedout the first transplantation of encapsu-lated cells in humans. ‘Using ECT, graftrejection by the host is prevented by thesemi-permeable barrier of the implant,’he explains. This work culminated in aPhase IIb trial for chronic pain in 1998.‘The intention was to block pain recep-tors and so reduce the chronic pain butthe trial ran into several problems,’ ex-plains Tom Shepherd, CEO at Neurotech.The device used was small, was implanted

in the spine, and the factor secreted (noradrenaline) was low in potency. Inthe large volume of fluid within the CNS, the factor could not build up tohigh enough levels to have an effect.Although the trial was a failure in somerespects, Shepherd stresses that the en-capsulation device itself was validated inthis trial, and that, with the right cellsand a high potency factor in a smallervolume of fluid, the trial might havebeen more successful.

One of the problems with the trial wasthe choice of cells; bovine cells wereseeded into the matrix of the im-plantable catheters. ‘Using xenobioticcells now poses ethical difficulties,’points out Shepherd and he confirmsthat current work to expand the appli-cations of ECT is based on human celllines that can live in an encapsulated matrix inside the body for at least 12months. At the moment, neither com-pany can discuss the details of the cellsbeing used but Shepherd confirms thatretinal cells are being used in the eye disorder studies. ‘It seems to make senseto use cells that normally live in the

environment that is under investigation,’he says.

ECT for eye disordersRebecca Li (Genetics Institute, MA, USA),who worked on ECT at Cytotherapeutics,developed several matrices specific fordifferent cell types. ‘The choice of encap-sulation matrix has a profound effect oncell morphology, level of factor secretedand viability of encapsulated cells,’ sheexplains. For example, when a collagen-coated polyethylene terephthalate (PET)yarn scaffold was compared with justcollagen, the results showed that the PETscaffold enabled cells to release fourtimes as much secreted ciliary-derivedneurotrophic factor (CNTF) comparedwith the collagen matrix1.

Shepherd and colleagues have nowstarted preclinical work in a caninemodel of retinal degeneration. ‘The dogmodel is providing information on howneuroprotective factors can protectagainst retinal damage,’ he reports.Dogs of a few weeks old have receivedimplants of encapsulated cells producing

Encapsulated cell technology providesnew treatment optionsKathryn Senior, Freelance writer

Figure 1. This shows the size of anencapsulated cell technology catheterfor use in the human eye comparedwith an ordinary pencil point.

Figure 2. This shows how the device ispositioned in the eye.

ImplantedECT device

Drug DiscoveryToday

CNTF. When injected into the eye, CTNFprotects neurones and retinal cells but atthe expense of serious side effects, saysShepherd. ‘Using retinal cells within adevice produces a very low level of sideeffects but enables high levels of CNTFto be delivered to the back of the eye,’says Shepherd. The 15-min procedure toimplant the small catheter causes lesspain than an injection and can be carriedout under local anaesthetic. In humans,the implantable eye device is tiny and is inserted directly into the vitreous humour (Figs 1 and 2). The position ofthe device can be checked regularlyusing an ordinary opthalmoscope and itcan be removed if there are problems. ‘Ifpreclinical work continues to go well, wecould go into Phase I/II clinical trials withinabout 14–18 months,’ says Shepherd.

ECT and Parkinson’sNSgene A/S are using ECT as a deliverysystem for factors to treat Parkinson’sdisease. Neublastin has already beenshown to protect dopinergic neurones(see Box 1). ‘ECT seems an ideal way ofdelivering neublastin across the blood–brain barrier; animal data and the PhaseIIb trial carried out by CytoTherapeuticsshowed good efficacy and low toxicity,’says Lars Wahlberg, COO at NSgene.

Insertion of the ECT device into thebrain is more invasive than in the eye butuses standard stereotactic techniques. Aframe is placed on the skull for referencepoints and then an MRI scan is used tocreate a system of coordinates to pin-point specific areas in the brain. Underonly a local anaesthetic, a small hole in

the skull is made through which acatheter is inserted. ‘Positioning the de-vice is crucial to the success of the therapy;we aim to place the tip of the catheterwithin the striatum, the area rich indopinergic neurones,’ says Wahlberg. Thecatheter is secured under the skin of theskull so that it is stable but can be re-moved. ‘This is a significant advantageof a delivery system over alternativessuch as gene therapy, which is usuallyimpossible to reverse,’ he points out.

The futureLysaght is encouraged by the progressbeing made so far. ‘The new collabora-tive studies avoid the pitfalls of earlierclinical trials with encapsulated cells,’ hesays. Both Shepherd and Wahlberg hopethat ECT implants will be permanent, orat least long lasting. ‘Even if the implanthas to be replaced annually, or every 18months, that would be acceptable tomost patients,’ predicts Wahlberg.

References01 Li, R. et al. (2000) Encapsulation matrices for

neurotrophic factor-secreting myoblast cells.Tissue Engineering 6, 151–163

02 Rosenblad, C. et al. (2000) In vivo protectionof nigral dopamine neurons by lentiviralgene transfer of the novel GDNF familymember neublastin/artemin. Mol. Cell.Neurosci. 15, 199–214

DDT Vol. 6, No. 1 January 2001 updatenews

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Box 1. Neublastin: a potentneuroprotective factor

Neublastin is a glial cell line-derived neurotrophic factor (GDNF).In vitro results have shown thatneublastin can increase the num-ber of surviving tyrosine hydroxyl-ase-immunoreactive neurones by≈70% when added to cultures of fetal mesencephalic dopamineneurones2. In vivo studies usinglentiviral vectors carrying cDNA forneublastin were injected into thestriatum and ventral midbrain ofrats and this was followed a weeklater by a selective lesion of the nigral dopamine neurones by anintrastriatal injection of 6-hydroxy-dopamine. Three weeks later, onlyabout 20% of the nigral dopamineneurones were left in the controlgroup, compared with 80–90% of dopamine neurones in theneublastin-treated group2.

Drug delivery collaborations……

Syngenix Ltd (Cambridge, UK) has signed an agreement with GlaxoWellcome (Research Triangle Park, NC, USA) for the

drug delivery of one of GlaxoWellcome’s drug candidates. Glaxo R&D will use the neuronal drug delivery technology from

SynGenix, ProVector, to target their drug for neuropathic pain directly to sites within the nerve. This system is hoped to en-

able much higher therapeutic doses to be achieved while minimizing the potential for adverse effects. The system is also said

to enable the delivery of large molecules that would otherwise be broken down in the body. The financial details of the

agreement were not disclosed.

Bradford Particle Design (BPD; Bradford, UK) has signed a licensing agreement with Bristol-Myers Squibb (BMS;

Princeton, NJ, USA) to provide BMS access to their supercritical fluid technology for controlling the formation of dry powder

particles. BMS paid BPD an undisclosed up-front licence fee for the knowledge and equipment, and for clinical trial materials

for specific collaborative projects. ‘Engineered pharmaceutical powders are playing an increasingly important role in

enabling new drugs and adding value to currently marketed products,’ said Ronald L. Smith, Director of Exploratory

Biopharmaceutics and Drug Delivery, BMS Research Institute. ‘This agreement strengthens our research and pharmaceutical

development platform by allowing us to apply proprietary technologies to our innovative drug products.’