Anti-KCNA1 monoclonal antibody Made to order

Refractory focal epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon optimized for human expression and mutated to accelerate the recovery of the channels from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a non-integrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled preclinical trial, the EKC lentivector robustly reduced seizure frequency in a male rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. When packaged into an adeno-associated viral vector (AAV2/9), the EKC gene was also effective at suppressing seizures in a male rat model of temporal lobe epilepsy. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as being ready for clinical translation in the treatment of refractory focal epilepsy.

The familial episodic ataxias are prototypical inherited channel opathies that result in episodes of vertigo and ataxia triggered by stress and exercise. Episodic ataxia type I (EA-1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA-2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A. These ion channels are crucial for both central and peripheral neurotransmission. Within the last few years, the genetic mechanisms underlying these relatively rare familial episodic ataxia syndromes have been worked out. They provide a model for understanding the mechanisms of more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine. Migraine affects as many as 15-20% of the general population, and it has been estimated that about 25% of patients with migraine experience spontaneous attacks of vertigo and ataxia. We identified 24 families with migraine and benign recurrent vertigo inherited in an autosomal dominant fashion. These families have numerous features In common with EA-I and EA-2 (particularly EA-2), suggesting that benign recurrent vertigo may be an inherited channelopathy. An ion channel mutation shared by brain and Inner ear could explain the combined central and peripheral features of the syndrome.