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Deepa Soundara Rajan, MD, and Jennifer L. Gannon, MD, discuss the current state of gene therapy for treating neurologic disorders.

Rare diseases affect more than 300 million people worldwide, and neurologic symptoms predominate in many patients. Therefore, general neurologists need to understand gene therapies—the therapeutic use of genetic material to treat or prevent disease—so they can identify and monitor their patients who are eligible for treatment.

“As treatments transition from clinical trials to clinical practice, the responsibility of identifying and monitoring patients may increasingly fall on the general neurologists. This evolving therapeutic landscape highlights the urgent need to enhance our understanding of this new class of medications and the details on clinical eligibility and monitoring of patients with diseases that have approved gene therapies,” researchers wrote in Neurology Genetics.

In a comprehensive overview of approved gene therapies for neurologic diseases, Deepa Soundara Rajan, MD, and colleagues also described the mechanisms and delivery methods of the gene-targeted therapies currently available for neurologic disorders.

Dr. Rajan and geneticist Jennifer L. Gannon, MD, who was not involved in the review, talked with Physician’s Weekly (PW) about ongoing advances in gene therapies for patients with neurologic disorders.

What are the key takeaways for practicing clinicians?

 Dr. Rajan: Genetic technology is revolutionizing diagnostics and rapidly introducing new therapies for children with rare neurologic diseases. Early diagnosis and prevention of neurologic damage are crucial to changing the outcomes of these diseases.

With new technologies come new opportunities and challenges. To make the best rapid impact, we need to educate ourselves on how to help kids with neurologic diseases get early diagnosis and access to novel trials and treatments. We also need to learn about the novel genetic therapeutics becoming available for these diseases.

Dr. Gannon: Many genetic neurodegenerative diseases have lacked disease-specific treatments. Gene therapies that have come to market and the number of drugs in clinical trials are developments that patients and families impacted by these diseases have long waited for.

However, some gene therapies aren’t without considerable risks. Knowledge about different gene therapy modalities and the risks, benefits, and ongoing monitoring for complications for each new drug pose new challenges for clinicians despite their expertise in neurodegenerative diseases.

What makes this review necessary now?

Dr. Rajan: Next-generation sequencing technologies have expedited our time to diagnosis in many rare pediatric neurologic disorders, and we now have increasing availability of new approved gene therapies and ongoing clinical trials for many of these diseases.

As more novel therapeutics in clinical trials move into clinical practice, it is crucial for general neurologists and even primary care physicians to familiarize themselves with this new class of medications. While each disease can have a specific gene therapy with individual clinical eligibility requirements, understanding this novel class of medications, its mechanism of action, and possible adverse events will be crucial for physicians who care for these patients clinically.

Dr. Gannon: The number of clinical trials and drugs coming to market will likely continue to increase. Clinicians must be familiar with different gene therapy modalities and specific drugs and drug trials in their area of expertise. Even if your patient is going to another center for treatment, initial discussions of their eligibility for treatment, risks, benefits, and long-term monitoring most often begin with you and the patient in the exam room.

Can you discuss the practical and ethical challenges of gene therapy?

Dr. Rajan: Novel gene therapies are bringing hope to the rare disease community with possible treatment options for diseases we didn’t previously have options for. However, the practical challenges include regulatory barriers and concerns about potential safety issues and long-term efficacy.

Also, the high costs of these approved drugs raise concern about differential access and the need for a paradigm shift in thought for funding these drugs. Ethical concerns and long-term effects are yet to be fully understood. Overall, addressing these issues as a community will be crucial in realizing the promise of these treatments.

Dr. Gannon: Differential access to gene therapy treatments is a significant concern. For instance, only five centers have the necessary expertise and experience from clinical trials to administer atidarsagene autotemcel therapy for metachromatic leukodystrophy.

Although centers and drug manufacturers are trying to ease the burden of travel, hospital stays far from home, and medical costs, many families still face challenges. Not all families have access to the Family and Medical Leave Act, and prolonged absences for travel and medical treatment could lead a patient or family member to lose income or their job altogether.

We need to have robust discussions about the expense of gene therapies, which contributed to the withdrawal of eli-cel [elivaldogene autotemcel] from Europe. Long-term safety monitoring is also crucial. While the incidence of hematologic cancers in 10% of eli-cel clinical trial participants is concerning and underscores the importance of continued monitoring of eli-cel trial participants, families whose child has early cerebral X-linked adrenoleukodystrophy and no match for stem cell transplant may be willing to take that risk.

How can addressing the knowledge gap, standardizing approaches to evaluating variants, developing regulated monitoring protocols for presymptomatic patients, and creating dedicated research and clinical infrastructure benefit patients who need gene therapy?

 Dr. Rajan: All these efforts will be crucial in practically realizing the promise of early, improved diagnosis of rare disease. We need to ensure consistency and reliability in test result interpretation, understand the natural progression of the disorders, and help with appropriate and timely intervention with novel therapeutics for patients who could benefit from them.

 Dr. Gannon: Newborn screening for some conditions has made the issue of what monitoring is needed for the presymptomatic patient apparent. How do we monitor for symptoms and identify when to treat without medicalizing the “patient in waiting”? It can sometimes take years of experience with these patients to understand how to best accomplish that.

Expert consensus statements and guidelines are essential in educating and directing clinicians on monitoring presymptomatic patients and those who’ve been treated and require long-term monitoring.

 What unanswered questions remain for you?

 Dr. Rajan: There are many unanswered questions. The rapid rise of technological improvements in diagnosis has broadened the spectrum of many disorders and unlocked opportunities. But the practical challenges of early presymptomatic diagnoses have exposed the need for us to come together as a clinical community to better understand, prevent, and treat these disorders.

The many imminent novel genetic therapies make it crucial for us to ask the right questions about the practical implementation, costs, and long-term follow up needed to better understand and implement the use of these treatments.

 Would you like to share any additional comments with clinicians?

 Dr. Rajan: Contrary to common belief, I think the role of a good clinician will dramatically increase in the era of AI and novel technologies. Good medicine is the art of not only understanding and implementing complex science but also of recognizing its limits and effectively communicating them to families. Clinicians need to build a collaborative environment of trust where each family can decide what is best for them and their children.