Special Report: Implantable delivery

An implantable device that delivers antibodies to target the amyloid pathology in Alzheimer’s disease.

Using advanced techniques for gene transfer, combined with materials for cell and tissue engineering, it is possible to generate an antibody-secreting implant for passive immunisation. This technology may help to fight against the deposition of aggregated proteins that accumulate in the brain, and which are some of the suspected causes of neurodegeneration. This research highlights the possibilities of gene and cell therapies to address the treatment of neurodegenerative diseases including Alzheimer’s.

Neurodegenerative diseases that affect the central nervous system are among the most important healthcare challenges, particularly in societies that face a progressive ageing of their population. Alzheimer’s disease, which is the most common form of dementia, has dramatic effects on the memory and other cognitive functions. As the disease advances, the people affected by Alzheimer’s lose their ability to execute even simple tasks in their daily life, and experience disorientation and changes in personality. The supporting families and caregivers face increasing difficulties to support the life quality of the affected patients. Most current treatments primarily target the symptoms of the disease and fail to address its cause. In particular, there is a dramatic lack of treatments able to slow down the progression of the disease.

Remarkably resilient

The difficulty to design an effective treatment is mainly due to our poor understanding of the pathologic processes leading to Alzheimer’s disease. The brain is an incredibly complex and poorly accessible organ. It is therefore difficult to monitor the changes that occur during the early stages of disease in the structure and function of the brain. In addition, the brain is remarkably resilient. Hence, it is often only when the disease has extensively damaged neuronal networks that the first symptoms are observed.

In the past few years, remarkable progress has, however, been made. A constantly increasing number of biomarkers as well as sophisticated imaging techniques have been developed to assess disease progression. A recognised feature of Alzheimer’s disease is the progressive and abnormal accumulation of misfolded proteins inside the brain. One of the first signs of the disease is the deposition of the amyloid beta (Aß) peptide both in blood vessels and inside the brain, forming extracellular plaques. Later, some neuronal networks also display neurofibrillary tangles, which are abnormal intraneuronal deposits of hyperphosphorylated and misfolded forms of another protein called ‘tau’. Although the exact sequence of events leading to these pathological manifestations has not been completely elucidated yet, there is a general assumption that treatments targeting the Aß and/or tau pathologies may have an impact on the progression of Alzheimer’s disease.

Immunisation against pathologic proteins as a treatment for Alzheimer’s disease

At this point, another major question arises: how can we therapeutically intervene in these pathogenic processes? The most advanced approach is the development of vaccines or antibodies able to generate specific immunity against the abnormal forms of these Aß and tau proteins. Proof-of-concept studies in preclinical animal models have shown that anti-Aß antibodies can reduce the amyloid burden in the brain, with a significant effect on the downstream consequences of this pathology. These results prompted a series of phase 1-3 clinical trials in Alzheimer’s patients, which have yielded mixed results, often considered as disappointing. Nevertheless, the most recent trials indicate that antibodies against Aß plaques may slow down disease progression when administered at an early stage of the disease, in prodromal and mild Alzheimer’s patients. In particular, recent trials with the antibodies Solanezumab, Crenezumab and Aducanumab have shown that significant beneficial effects can be achieved, with a decrease of amyloid plaque deposition and, more importantly, a slower rate of cognitive decline. However, these treatments require high-dose bolus injections of recombinant antibodies every month. This could pose problems if the treatment needs to be administered for years, even before the onset of the cognitive impairments.

In order to develop effective therapeutics for the central nervous system, it is critically important to design technologies to deliver molecules in the right place at the right time, with minimally invasive procedures. The delivery of antibodies to the central nervous system is difficult, because only a small fraction of these molecules circulating in the blood will penetrate the blood-brain barrier and reach their target inside the brain. In addition, immunisation procedures against Aß have caused adverse effects. Active anti-Aß vaccines led to meningoencephalitis, a major side effect which has strongly limited this approach. In contrast, passive immunisation by injection of recombinant anti-Aß antibodies is much better tolerated. However, monitoring of patients by MRI imaging 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

Dr Bernard Schneider
Brain and Mind Institute
Ecole Polytechnique Fédérale de Lausanne (EPFL)
+41 21 693 95 05
[email protected]
http://len.epfl.ch/