NFP37 SOMATIC GENE THERAPY Divulgation Abstracts phase B

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AEBISCHER, Patrick	CHUV, Division Recherche chirurgicale et centre de therapie genique, Pavillon 4, 1011 Lausanne tel 021 314 2462; fax 021 314 2468 e-mail: patrick.aebischer@chuv.hospvd.ch
Title:	Development of a gene therapy approach for patients suffering from amyotrophic lateral sclerosis
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DIVULGATION TEXT AT SUBMISSION 1997:

Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. One neurotrophic factor in particular, ciliary neurotrophic factor (CNTF), has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial clinical trial focusing on the systemic administration of CNTF resulted in severe side-effects mandating the interruption of the trials, therefore preventing determination of the efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which 10 patients with ALS were implanted with polymer capsules containing geneticallyengineered baby hamster kidney (BHK) cells releasing approximately 1.0 µg of CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Serial cerebrospinal fluid (CSF) sampling showed the presence of hundred of picograms of CNTF up to 15 months post-implantation whereas no CNTF was detected prior to implantation. On explant, devices showed viable BHK cells and CNTF output when measured in vitro. The patients showed no weight loss, severe coughing or induction of acute phase reactants over the course of implantation which were the limiting side effects observed with systemic CNTF administration. All patients were evaluated using various ALS clinical rating scales for ALS progression. Examination of the slopes of the various tests before and after implantation indicate that the disease continues to progress. In vitro and experiments conducted on rodent models of motoneuron degeneration indicate that the delivery of more than one trophic factor has beneficial effect over the delivery of a single factor. We have identified a second neurotrophic factor named NT4/5 which synergises in vitro the effect of CNTF. We have also been able to construct cell lines able to release 2 trophic factors. These cell lines are currently being tested in various animal models of motoneuron degeneration. It is hoped that these combinations can be tested in patients in the not so far future.

Neurotrophic factors are proteins that hold promise for the treatment of neurodegenerative diseases. Demonstration of the neuroprotective effects of trophic factors in the central nervous system (CNS) and in various animal models of neurodegeneration has led to the development of strategies for the treatment of diseases such as Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS). The presence of the blood brain barrier, a system that prevent the access of molecules including proteins to the nervous system remains, however, a major concern for the delivery of neurotrophic factors to the CNS. A technique involving the placement of cells genetically engineered to release neurotrophic factors in natural fluid surrounding the spinal cord provides a means to continuously deliver trophic factors directly within the CNS, beyond the blood brain barrier. The cells are protected from the host immune system by a thin porous synthetic film that we call capsules.
Amyotrophic lateral sclerosis is a neurodegenerative disease leading to paralysis and death within 2-3 years following the loss of motoneurons, the nerve cells localized essentially in the spinal cord controlling muscle activity. Administration of neurotrophic factors in vitro and in animal models of this disease lead to an increased survival of motoneurons. Numerous side effects have been observed following systemic administration in ALS patients of human ciliary neurotrophic factor (hCNTF), a trophic factor. Deliver of hCNTF should directly expose motoneurons to the neurotrophic factor, while avoiding side effects related to its peripheral administration. This can be achieved by the transplantation of immunoprotected xenogenic cell lines genetically engineered to release hCNTF.
The efficacy and safety of transplanting baby hamster kidney (BHK) cells genetically engineered to release human CNTF was first demonstrated in rodents and sheep. Twelve patients were then implanted in the fluid surrounding hte spinal cord with a device containing BHK cells releasing CNTF. According to the protocol, the implants have been retrieved after 3 months and replaced by a second capsule. Viable cells and hCNTF secretion were observed in all retrieved implants. No limiting adverse effects were observed in any of the implanted patients. Detectable levels of CNTF were observed up to 60 weeks post transplantation whereas hCNTF was undetectable before implantation. The biological results demonstrate that neurotrophic factors can be delivered to the CNS through encapsulated genetically modified cel1 transplantation. The small number of patients, however, does not allow the assessment of a potential slowing of the degeneration process.

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