Advancing Gene Therapies for Rare Neurological Diseases

Neuroscience is entering a new chapter shaped by advances in genetic medicine, more adaptive regulatory frameworks and deeper insight into the biology of neurological disorders.

More than 300 million people around the world are affected by rare diseases, and nearly half of these involve the nervous system. Approximately 80% of rare diseases have a genetic basis, yet most still lack effective treatment options.

Meanwhile, neurological conditions in general impact over 3 billion people worldwide, making them the leading cause of global disability and disease burden.

Gene therapies are gaining traction as a promising approach for treating rare and complex neurological disorders. As of now, 45 cellular and gene therapy products have received FDA approval, including 22 FDA-approved gene therapies and multiple examples targeting neuromuscular and central nervous system (CNS) disorders.

Gene therapies developed for orphan diseases have shown notably higher success rates across all stages of clinical development compared to the average drug. These therapies are 48% more likely to advance past Phase I, 65% more likely to succeed in Phase II, and 30% more likely to complete Phase III.

Even during regulatory review, orphan gene therapies outperform, with a 10% higher likelihood of successfully completing a New Drug Application (NDA) or Biologics License Application (BLA). This underscores their potential to address conditions that were previously untreatable.

Dr. Norman Putzki, Senior Vice President and Global Development Head of Neuroscience and Gene Therapy at Novartis, spoke with Xtalks about how his team is addressing the challenges of developing gene therapies for rare neurological diseases.

He shared insights on patient-focused drug development, trial design tailored to rare conditions and strategies for delivering these therapies to the patients who need them most.

Xtalks Clinical Edge™: Issue 5 — Gene Therapy Innovation for Rare Neurological Disorders at Novartis

Xtalks Clinical Edge™ is a magazine for clinical research professionals and all who want to be informed about the latest trends and happenings in clinical trials. This magazine immerses you in a world where industry leaders, patient advocates and top researchers converge to provide the most insightful perspectives on clinical trials.

From Clinic to Global Development

Before joining Novartis, Dr. Putzki led academic research and clinical programs focused on CNS disorders, particularly multiple sclerosis. His decision to transition from academia to industry wasn’t a single leap — rather, it was the result of long-term reflection on how to make a broader impact.

“It wasn’t just this one moment where I felt I’m going to do this,” he explained. “It was really the result of a longer term, almost evolutionary kind of process.”

Dr. Putzki described how his motivation remained consistent across both settings: a desire to improve the lives of patients.

“You want to provide a solution to that patient sitting in front of you, the family, helping them lead a better life with whatever condition they have,” he said. “And when I made that decision to step into industry, it was exactly the same question. I wanted to do this not just for the single patient sitting in front of me, but on a larger scale.”

That same mission continues to guide his work today, as he leads global teams advancing neuroscience drug development at Novartis — including efforts to bring forward new gene therapies that address some of the most serious and underserved neurological conditions worldwide.

Reimagining Medicine Through Genetic Innovation

Novartis’ mission to “reimagine medicine” is embedded in its strategic focus on neuroscience, one of its four core therapeutic areas.

“We follow where the unmet need is. It’s not about checking boxes. It’s about where we can drive the most meaningful change for patients and society.”

— Dr. Norman Putzki

Rather than centering on rare diseases alone, Novartis identifies areas with significant unmet medical need — regardless of prevalence — and assesses where its internal capabilities and global footprint can make the greatest impact.

This strategy has led to progress in spinal muscular atrophy (SMA), where Novartis recently reported positive results for a next-generation gene therapy.

The company’s genetic medicine pipeline continues to grow, with programs expanding into other serious, underserved conditions such as cystinosis, a rare metabolic disease.

“We follow where the unmet need is,” explained Dr. Putzki. “It’s not about checking boxes. It’s about where we can drive the most meaningful change for patients and society.”

Patient-Centric by Design

At Novartis, patient-centricity isn’t just a buzzword — it’s a guiding principle embedded throughout the drug development lifecycle.

From early discovery through regulatory submission and commercialization, patient input plays a critical role in shaping clinical programs and ensuring that they reflect real-world needs.

“We standardize patient engagement at multiple milestones,” said Dr. Putzki.

“For example, through patient advisory boards. It’s very important to discuss with patients directly if we’re solving for the right problem. An endpoint that is acceptable for the FDA may not be exactly the endpoint that the patient community is concerned about.”

He emphasized that designing around the regulatory framework alone can leave gaps in addressing what truly matters to patients. By bringing patient voices into the process early and often, Novartis aims to build programs that are not only scientifically rigorous but also relevant and practical for those living with the disease.

For rare disease studies in particular, where patient populations are small and highly engaged, trial burden is a major consideration.

Input from advocacy groups and caregivers helps shape protocols that include meaningful endpoints, reduce logistical and emotional strain, and ultimately support faster, more successful trial execution.

Evolving Trial Designs for Rare Neurological Diseases

The COVID-19 pandemic accelerated the shift toward decentralized and hybrid clinical trial models, and Novartis has continued to carry this momentum forward.

The company routinely incorporates decentralized components such as virtual patient visits, remote data collection and monitoring and virtual audits — all of which help reduce the burden on participants and trial sites while maintaining data integrity and operational efficiency.

Dr. Putzki explained, “Novartis was well positioned that when the pandemic happened, we pretty quickly could shift from the classic operating model with, for example, patient visits in the clinic to a virtual model or at least a hybrid model. We could introduce virtual audits for data quality and data integrity and all of these kinds of things.”

He also noted that these practices are no longer temporary adjustments but are becoming embedded into trial design thinking. “So for us today, it’s standard to think of those options in terms of what’s the best least burdensome opportunity to study,” he said.

For rare neurological diseases — where patient populations are small, geographically dispersed and often face mobility or access challenges — these flexible models are especially important.

In parallel, conversations with regulators now frequently focus on the use of surrogate or biomarker endpoints, opportunities for accelerated review and the integration of real-world data. These approaches aim to speed up access to new therapies while maintaining high standards of scientific rigor.

Working Together to Advance Neuroscience

Dr. Putzki emphasized that advancing treatment for neurological diseases requires much more than internal discovery — it depends on close collaboration across the broader healthcare and life sciences ecosystem.

From academic labs and small biotech startups to regulatory agencies, patient advocacy groups and healthcare providers, every stakeholder plays a vital role in bringing innovative therapies to patients.

“There’s incredible science happening outside Novartis, and we see it as our responsibility to help advance it. That might be through strategic collaborations or applying our experience to accelerate external innovation.“

— Dr. Norman Putzki

He noted that large pharma companies can play a critical role in supporting smaller organizations, particularly those developing promising early-stage science that may lack the infrastructure or resources to reach patients on their own.

“We are really trying to figure out, when we think about collaborations, what is our role in facilitating some of the innovation that we are most excited about inside of Novartis, but then also in the broader ecosystem.”

Beyond R&D partnerships, regulatory collaboration is especially critical in the context of gene therapy and rare diseases, where clinical trials often involve very small patient populations and unique challenges.

Dr. Putzki shared the example of a recent clinical program for a next-generation SMA treatment, which required an intrathecal delivery and a sham-controlled design — an ethically and operationally complex approach, particularly in a pediatric population.

“You can imagine what that means for a patient. Patients are between two and 18 years old — what it means to sign up for a trial where you are either receiving the actual treatment or sham treatment. It’s a huge patient burden,” he explained. “In an ideal world, however, we would not have to do that. I think there might be other ways to do it.”

He added that working more flexibly with regulators could open the door to alternative study designs and approval pathways that are both scientifically valid and less burdensome for participants. Building these pathways, he said, is key to accelerating progress while upholding ethical and clinical standards.

Transformative Era for Neuroscience

The future of neuroscience, according to Dr. Putzki, resembles oncology in the 1990s — a field on the verge of rapid expansion and breakthroughs.

Among the most promising areas:

• Targeted therapies for neurodegenerative diseases like ALS, Parkinson’s and Alzheimer’s, where delivery methods and target engagement are central challenges
• Next-generation AAV vectors, which aim to improve the safety and efficacy profile of gene therapies
• Regulatory innovation, including the use of surrogate endpoints, confirmatory data collection post-approval and alternative trial designs
• CRISPR-based therapeutics, which remain in early days but hold potential to address genetically defined neurological disorders

But perhaps the greatest bottleneck remains the blood-brain barrier — and how to overcome it non-invasively.

“If we can solve delivery into the CNS without surgery, we can unlock transformative therapies across a range of conditions,” said Dr. Putzki.

Looking Ahead

As Novartis continues to invest in neuroscience, the pipeline reflects both depth and foresight.

From expanding programs in genetic medicines to advancing next-gen neurology treatments, the company is poised to lead in what Dr. Putzki confidently calls “the golden age of neuroscience.”