Periodic Reporting for period 1 - NOGOPROOF (Towards clinical trials for a novel treatment for stroke)
Période du rapport: 2017-03-01 au 2018-08-31
A major problem in Neurology is the fact that the adult brain has a very limited capacity to repair large lesions. Stroke is a very frequent brain lesion, which is caused by vascular problems like bleedings or vessel blockade by a thrombus. Larger strokes result in life-long disability, in particular hemiplegia, loss of speech, and cognitive disturbances. Except for early interventions, for which only about 10% of the stroke patients are eligible, and for rehabilitation, no treatments able to improve the outcome of large strokes are available. Stroke patients thus often suffer from an important loss of quality of life; the socio-economic costs of stroke a very high.
In the previous ERC advanced grant project ‘Nogorise’ we could show that antibody-mediated neutralization of the nerve fiber growth inhibiting membrane protein Nogo-A, which is present in the myelin sheets of the adult brain and spinal cord, leads to enhanced growth and regeneration of fibers in the injured brain and spinal cord. In animals with large strokes and massive deficits of fine motor control, an almost complete functional recovery could be obtained with a 2 wk antibody therapy. Antibodies were applied directly into the cerebrospinal fluid because these large molecules cannot reach the brain tissue from the blood due to the blood-brain-barrier. In the present project, we investigated if large doses of anti-Nogo-A antibodies can reach and penetrate into the injured brain after a large cortical stroke in adult rats. While a certain degree of brain penetration was present in the first few days after the stroke, intracerebral levels fell rapidly thereafter. The functional recovery of skilled forelimb grasping was poor in the animals, as compared to rats which received direct intrathecal antibody administration. We conclude that the future clinical protocol of anti-Nogo-A antibody therapy in stroke has to include a drug administration directly into the cerebrospinal fluid by an intrathecal route.
To translate these findings from the animal to the patient level, fully human anti-human Nogo-A antibodies were selected from human B-cell libraries and characterized. Candidates with excellent biochemical properties were obtained; they are currently investigated for their recovery enhancing properties in an established model of large cortical strokes in adult rats. The project has been taken over and is promoted from now on by a spin-off company of the University of Zurich, Novago Therapeutics Inc.. A drug optimization and production plan is in place, the clinical development strategy and market analyses are currently being formulated, as well as the required regulatory document portfolio to enter the stage of clinical testing in stroke patients as soon as possible.
In the previous ERC advanced grant project ‘Nogorise’ we could show that antibody-mediated neutralization of the nerve fiber growth inhibiting membrane protein Nogo-A, which is present in the myelin sheets of the adult brain and spinal cord, leads to enhanced growth and regeneration of fibers in the injured brain and spinal cord. In animals with large strokes and massive deficits of fine motor control, an almost complete functional recovery could be obtained with a 2 wk antibody therapy. Antibodies were applied directly into the cerebrospinal fluid because these large molecules cannot reach the brain tissue from the blood due to the blood-brain-barrier. In the present project, we investigated if large doses of anti-Nogo-A antibodies can reach and penetrate into the injured brain after a large cortical stroke in adult rats. While a certain degree of brain penetration was present in the first few days after the stroke, intracerebral levels fell rapidly thereafter. The functional recovery of skilled forelimb grasping was poor in the animals, as compared to rats which received direct intrathecal antibody administration. We conclude that the future clinical protocol of anti-Nogo-A antibody therapy in stroke has to include a drug administration directly into the cerebrospinal fluid by an intrathecal route.
To translate these findings from the animal to the patient level, fully human anti-human Nogo-A antibodies were selected from human B-cell libraries and characterized. Candidates with excellent biochemical properties were obtained; they are currently investigated for their recovery enhancing properties in an established model of large cortical strokes in adult rats. The project has been taken over and is promoted from now on by a spin-off company of the University of Zurich, Novago Therapeutics Inc.. A drug optimization and production plan is in place, the clinical development strategy and market analyses are currently being formulated, as well as the required regulatory document portfolio to enter the stage of clinical testing in stroke patients as soon as possible.