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Pan European Networks: Science & Technology

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203

PROFILE

Dr Bernard Schneider

Brain and Mind Institute

Ecole Polytechnique Fédérale de Lausanne (EPFL)

+41 21 693 95 05

bernard.schneider@epfl.ch http://len.epfl.ch/

antibodies is much better tolerated. However, monitoring of

patients by MRI has revealed the occurrence of amyloid-related

imaging abnormalities (ARIA) in patients following high dose

injection of these antibodies. ARIA is thought to represent

vasogenic edema, which can sometimes be associated with

transient symptoms.When ARIA is observed, the treatment may

need to be discontinued or adjusted.

Encapsulated cell technology for continuous

antibody delivery to the brain

One approach to avoid these limitations is to develop a delivery

system to achieve continuous administration of the antibody, and

therefore avoid the peak concentrations that can lead to side

effects. Gene therapy may provide such a solution. The

implantation of a renewable cell source genetically modified to

produce recombinant antibodies can be used to constantly

release a specific antibody into the bloodstream or the

cerebrospinal fluid. Genetic engineering can turn cell types that

do not naturally secrete antibodies into effective antibody

producers. For instance, renewable cells derived from the skeletal

muscle can secrete high levels of functional antibodies targeting

the Aß peptide. The use of an implantable device made of

polymer permeable membranes to ‘encapsulate’ the cells

provides further key advantages. As the permeable membrane

shields the implanted cells from any cell-to-cell contact with the

host immune system, a universal, well-characterised cell source

can be used for all recipients without the need for any

immunosuppressive treatment to prevent immune rejection. In

addition, the capsule contains a predictable number of cells.

Hence the amount of antibodies delivered can be estimated and,

in case of adverse event, the device can be easily retrieved.

When the device is implanted in the subcutaneous tissue, the

antibodies produced are transported via the bloodstream. A

fraction of these antibodies can enter the brain and bind amyloid

plaques. In mouse models, continuous antibody administration

for several months during disease development has dramatic

effects on the brain pathology. Antibody binding, which is likely to

recruit immune microglial cells at the site of amyloid deposition,

prevents plaque formation.When the amyloid pathology is

substantially decreased, downstream pathological events,

including the hyperphosphorylation and misfolding of the tau

protein, can also be reduced. In some instances, it could be

desired to reach high antibody levels inside the central nervous

system. To address this need, a device can be similarly designed

for implantation of the antibody-secreting cells inside the brain, to

deliver antibodies

in situ.

This approach is one example of the various techniques that gene

therapy can offer nowadays to address the treatment of

neurodegenerative disorders. Genetic engineering has made

tremendous progress, providing very effective techniques for

de

novo

gene expression, gene silencing and, more recently, gene

editing. The development of effective vectors for gene transfer,

often derived from existing viruses, allows long-term gene delivery

to the adult central nervous system.When combined with

advanced techniques for cell and tissue engineering, gene therapy

can provide very efficient means for therapeutic intervention in

complex organs, such as the brain and spinal cord. All these

techniques are now gaining attention and are likely to become

part of the needed therapeutic arsenal to tackle the challenge of

neurodegenerative disorders.

References

Lathuilière,A. Laversenne,V.Astolfo,A. Kopetzki, E. Jacobsen, H. Stampanoni, M.

Bohrmann, B. Schneider, B.L. & Aebischer, P. (2016)

A subcutaneous cellular implant for passive immunization against amyloid-ß

reduces brain amyloid and tau pathologies.

Brain,

pii: aww036

PMID: 26956423

Lathuilière,A. Cosson, S. Lutolf, M.P. Schneider, B.L. & Aebischer, P. (2014)

A high-capacity cell macroencapsulation system supporting the long-term survival

of genetically engineered allogeneic cells.

Biomaterials,

35(2):779-91.

PMID: 24103654

A subcutaneous cellular implant containing cells genetically

engineered for the production of antibodies against Aß: a technology

for passive immunisation against Alzheimer’s disease

THE HUMAN BRAIN