Could iPSCs Be The Answer To Treating CNS Disorders?

A conversation with Jeffrey M. Brown, Ph.D., MBA, CSA, Neurizon Therapeutics

Central nervous system (CNS)-related disorders are widespread around the world. Over 1 in 3 people are affected by neurological conditions, making it the leading cause of illness and disability worldwide. The inability of therapeutics to access the central nervous system has remained a major barrier in the treatment of neurodegenerative diseases. However, patient-derived induced pluripotent stem cells (iPSCs) could be the key to treating CNS disorders.

In this Q&A, Life Science Connect’s Michelle Raley caught up with Jeffrey M. Brown, Ph.D., MBA, scientific advisor at Neurizon Therapeutics, to discuss the company’s approach with drug candidate NUZ-001and the advice he shares with industry.

New rodent preclinical pharmacokinetic (PK) data demonstrates that NUZ-001 and its major active metabolite (NUZ-001 Sulfone) effectively cross the blood-brain barrier (BBB), which is difficult to achieve. Can you share some of the implications and interpretations of these findings?

The results from these preclinical studies represent an important finding for Neurizon, as we address some of the biggest hurdles in developing drugs for neurological conditions. Here's a breakdown of the implications.

The primary challenge for most CNS drug candidates is their inability to cross the BBB. The BBB is a natural protective barrier that prevents chemicals from crossing between the plasma and the brain compartment. This includes therapeutic compounds and compounds in development. By demonstrating that NUZ-001 and its metabolite NUZ-001 sulfone successfully cross the BBB, Neurizon has overcome a major obstacle in CNS drug discovery and increased the excitement around the potential use of this compound for other CNS indications.

The study didn't just show that the drug crossed the BBB; it also demonstrated that NUZ-001 and the sulfone metabolite reached levels in the brain consistent with levels used in preclinical models to show a positive effect. This is a critical distinction, as it indicates the drug is not only getting into the brain but is doing so at a therapeutically relevant concentration.

Finally, the findings also serve as a powerful validation of Neurizon’s strategy. By starting with a known compound with established physicochemical properties and a validated safety profile in veterinary applications, Neurizon was able to quickly advance this compound. This approach provides a significant start, allowing the company to accelerate its research and development timelines.

How is Neurizon tackling challenges associated with patient-derived induced pluripotent stem cells?

iPSCs are a powerful tool as they allow us to create disease models that directly reflect human biology. By reprogramming cells from a patient and leveraging human-derived neuronal lines containing causative genetic mutations, we can evaluate our compounds in neurons that are linked to human biology. However, as you noted, these models come with significant challenges. They require highly specialized expertise, are expensive to maintain, and can exhibit high variability from one patient's cell line to another. These factors can slow down research and make it difficult to scale.

To circumvent this, Neurizon leverages a tiered and integrated approach that combines rigor with efficiency. First, we start with more scalable and cost-effective models, such as standard immortalized cell lines or simpler animal models like zebrafish. These systems allow us to rapidly screen many drug candidates and identify the most promising ones. This initial phase helps us quickly narrow down our options and design more targeted experiments.

Once we have a smaller, more promising set of candidates, we then move to the more complex and biologically relevant iPSC-derived neuron models. This is where we confirm our key findings and get a more accurate picture of a drug's activity in a human-relevant context. This step is critical because it validates that the drug's effect is not just a fluke but is likely to translate to the disease's biology in a patient.

By using this integrated approach, Neurizon achieves a strong cost-benefit balance. We leverage the speed and efficiency of simpler systems for early-stage screening, which allows us to be more strategic and cost-effective with the more resource-intensive iPSC models. This ensures that our science remains closely tied to patient biology without sacrificing the speed and efficiency needed to advance our drug candidates.

What is your approach toward translational validation in early R&D?

Our approach to translational validation is a systematic process designed to build a clear and reliable bridge from preclinical findings to real-world patient benefits. This can be defined by our three pillars of research strategy.

First, our discovery process starts with a foundation of human biology. As stated above, we leverage induced pluripotent stem cells, which contain relevant human disease-causing mutations. This allows Neurizon to study the disease in a context that is far more relevant to a human patient than a typical animal model. In amyotrophic lateral sclerosis (ALS), for example, we can directly measure the reduction of TDP-43 protein aggregates, a key pathological hallmark of the disease, within these patient-derived cells. This approach increases the probability that our early findings will hold true when we move into human clinical trials.

Second, we establish a clear link between a drug's presence in the body and its therapeutic effect. We track a drug's PKs and how much of the drug gets into the brain, then correlate with the pharmacodynamic (PD) effects we observe such as the reduction of protein aggregates. This step is crucial because it confirms that the biological benefits we see are directly tied to the concentration of the drug that we can safely and realistically achieve in patients.

Third, we leverage assays and biological readouts that can be used both preclinically and clinically. For example, we have shown that NUZ-001 can reduce TDP-43 aggregates in a human iPSC-derived cellular model. TDP-43 is being investigated as a biomarker of drug effects in clinic, allowing for a potential translatable link. We also think holistically about other opportunities that can be directly translated from preclinical models to clinical readouts. These include electrophysiological readout (a measure of neuronal network activity), fluid biomarkers, and biochemical changes in blood cells that can be used as a target engagement indicator.

This integrated approach of human-based biology, PK/PD modeling, and leveraging clinically relevant biomarkers preclinically allows for a more direct translation of the preclinical data to clinical trials.

What’s your advice for other companies developing drugs to treat neurodegenerative disorders?

Over the years, drug discovery strategy swung from broad “does it work?” approaches, which leveraged phenotypic screening in disease models and compounds with previously reported efficacy, to extremely focused single-target design. This approach proved effective for developing compounds to treat cancer, infectious diseases, and monogenic diseases. However, brain diseases are complex. The brain is designed to have redundant and complex neural circuits with overlapping targets, each having distinct functions depending on location and context. Moreover, CNS disorders are multifactorial and often represent a biological spectrum rather than a single-defined disease. To address CNS disorders, including neurodegenerative diseases, a balanced approach works best:

• Blend target-based and phenotypic testing. Start with strong biology about a pathway you can influence, then also run outcome-focused screens (in cells and animals) to catch helpful effects you didn’t predict.
• Design for the brain early. Prioritize properties that let a medicine reach the brain at safe, effective levels and stay there long enough to matter.
• Use patient-relevant models wisely. Combine faster, lower-cost systems to narrow options with more complex models (like patient-derived neurons) to confirm what really translates.
• Leverage already proven compounds when possible. Beginning with molecules that already have known “drug-like” features can save time, cost, and risk.
• Measure what matters. Build in biomarkers and functional readouts that connect lab results to patient benefit.

This is the path we’ve taken at Neurizon: identify compounds with well-understood drug properties, target biology linked to neurodegeneration, and continue building on existing safety. We’re seeking to advance NUZ-001 as a potential therapy, guided by data from both targeted and phenotypic studies.

About The Author

Jeffrey Brown is a seasoned biotech leader with over 20 years of experience translating scientific discoveries into potential medicines for neurological diseases. He has guided more than 20 preclinical programs, successfully advancing several into clinical trials. He is trained as both a scientist (Ph.D.) and business executive (MBA). Brown has held leadership roles at Pfizer, Amgen, and Bristol-Myers Squibb, where he built teams and strategies spanning discovery, translational biology, and early development.

He is the founder and CEO of Scientific Foundation LLC and serves as chief scientific advisor at Neurizon Therapeutics, a clinical-stage company dedicated to advancing innovative treatments for neurodegenerative diseases.