Exploring Cell Therapy for the Treatment of Drug-Resistant Epilepsy

Neurona Therapeutics is developing cell therapies for the treatment of central nervous system disorders, starting with their lead program NRTX1001, a fully differentiated, medial ganglionic eminence (MGE), inhibitory neuron cell therapy for the potential treatment of drug-resistant mesial temporal lobe epilepsy. The cell therapy is designed to deliver the inhibitory neurotransmitter GABA to calm hyperactive neuron circuitry.

NRTX1001 is set to be evaluated in a phase 1/2 clinical trial (NCT05135091) that will soon begin enrollment in trial sites across the US. The cell therapy has previously demonstrated safety and efficacy in preclinical studies, with reductions in seizures and disease pathology observed.

CGTLive spoke with Cory Nicholas, PhD, cofounder and chief executive officer, Neurona, to learn more about Neurona’s cell therapy platform and the first in-human clinical trial. He discussed the potential that this new approach may hold for the treatment of epilepsy.

CGTLive: Tell me about Neurona’s cell therapy platform and first cell therapy candidate.

Cory Nicholas, PhD: We have a unique cell platform lineage called an MGE cell; it's a lineage that the Neurona founders have studied for decades that has the unique capacity to functionally integrate at the level of the synapse and to modulate neural circuit activity in a homeostatic, reparative way. The first product is an inhibitory nerve cell or neuron that delivers the inhibitory neurotransmitter GABA and is adept at providing this inhibitory tone to rebalance hyperactive neural circuits. It's the first product to our knowledge that is developing inhibitory cell therapy with this class of inhibitory neurons, so it'sa very unique platform and lineage the company's pursuing as the basis for its initial pipeline.

NRTX1001 as well as the other MGE platform lineages are again unique because they integrate into circuitry and they establish synapses with the recipient’s nervous system and cells. They don't stay as a cell mass at the site of delivery, they actually migrate and integrate into the tissue and become seamlessly part of that network, and because of that, they persist very well and they become regulated by the recipient’s nervous system. Because of this, we've seen no dose-limiting toxicitiesin our preclinical studies. They appear to be very safe therapies in these preclinical models, and they're very potent effectors of rebalancing and repairing those neural circuits that become hyperactive, for example, in epilepsy.

Why is there such a need for new treatment options in this population?

The first indication for this NRTX1001 inhibitory nerve cell therapy product is for the treatment of drug-resistant epilepsies, particularly epilepsies that start in one part of the brain and the most common type of epilepsy is temporal lobe epilepsy. These seizures typically begin in one temporal lobe in the hippocampus, before they spread more globally, and result in classic tonic-clonic seizures.

For people who have drug resistant epilepsy, there aren't many options. Epilepsy is known to be highly drug-resistant, as about a third of people with epilepsy do not respond effectively to anti-seizure drugs and are left in this chronic drug-resistance state without good options. For some people that have seizures that begin in the temporal lobe, there is surgery as an alternative that removes or destroys that part of the brain. It can be effective for some people, but it carries a high risk of significant irreversible adverse effects on memory, mood, and vision, and so often is seen as a last resort, because it'sdestructive, and it damages not just the seizure focus but surrounding healthy tissues. Moreover, there are many people with chronic drug-resistant epilepsy of this type who are not eligible because surgery may not be feasible in their brain’s seizure onset zone.

In contrast, cell therapies are not tissue destructive, they're regenerative. They're reconstructing the damaged inhibitory cells to provide regulation to those circuits and to stop the onset and propagation of seizures. There’s a huge need for an alternative to surgery, something that is targeted, non-destructive, hopefully safer, and that potentially has the chance to be curative from a single dose. In our preclinical studies, we've seen dramatic rescues in most of the preclinical models treated with the cell therapy – over two thirds of the treated group became completely seizure-free and the therapy has been very safe. Our team has gone to great lengths to make sure that the cells are controlled and don't expand after administered. In fact, there are no remaining stem cells in our products. They are fully differentiated, authentic inhibitory nerve cells intended to replace the endogenous nerve cells that had degenerated with the disease.

To the best of our knowledge, this is the first human cell therapy that's being investigated in clinical trials for epilepsy. So, it's an exciting time for the refractory epilepsy community that hasn't really had new approaches other than destructive surgeries, small molecule drugs, or stimulators that haven't been totally effective. In the epilepsy space, the goal is truly to achieve seizure freedom and a cure, because even a few seizures can be quite disabling to these people's lives. If they have just 1 or 2 seizures a year they can't drive or work. Most of the clinical sites we're working with are quite excited by having this new modality.

I think it's going to be very exciting for the field as they learn about the work we're doing. I think the Neurona team has done an amazing job in harnessing stem cell and regenerative technologies to make these product candidates. It's unprecedented in the great lengths they’ve gone to to ensure safety. Again, our cell therapies do not contain stem cells; they contain fully differentiated authentic types of MGE neuro lineages that are not expanding. We've put them through their rigors to make sure that they're not harmful in preclinical models. We're entering this clinical trial with a sense of not doing harm and safety being paramount for any first in-human trial, and we remain cautiously optimistic that the cells areactually going to be effective and have significant disease-modifying activity.

Transcript edited for clarity.