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Advances in Therapeutic Drugs for Pediatric Neurological Disorders: How Gene Therapy and Nucleic Acid Medicine Have Changed 'Untreatable Diseases'

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Hello, this is the 'Children's Brain Lab'.

'There is no treatment for this disease.'

Until very recently, this was the only thing doctors could tell parents regarding many pediatric neurological disorders.

However, the situation has been changing dramatically over the last 5 to 10 years. With the emergence of new treatment methods such as gene therapy and nucleic acid medicine, we have entered an era where diseases once considered 'untreatable' can now be treated.

In this article, we will explain the progress of therapeutic drugs for pediatric neurological disorders in a way that is easy for parents to understand.

📌 What you will learn in this article

  • What enzyme replacement therapy, gene therapy, and nucleic acid medicine are, and why they are groundbreaking

  • Which diseases now have therapeutic drugs (SMA, DMD, AADC deficiency, etc.)

  • Why early detection and early treatment are important

  • The expansion of newborn mass screening

  • New challenges brought by advances in treatment and the importance of multidisciplinary care at specialized facilities


🔹 Why is the treatment of neurological disorders changing now?

The difference between conventional and new treatments

Many pediatric neurological disorders occur because a specific genetic abnormality prevents the body from producing necessary proteins.

Conventional treatment focused on 'symptomatic therapy.' While it could alleviate symptoms, it could not cure the root cause of the disease.

New treatment methods approach this 'root cause'.

Enzyme Replacement Therapy (ERT) — The first 'curative treatment'

Entering the 2000s, Enzyme Replacement Therapy (ERT) emerged. This is a treatment method where the enzyme that the body can no longer produce is periodically replenished via intravenous infusion.

Representative diseases and therapeutic drugs:

  • Pompe disease: Alglucosidase alfa (Myozyme), approved in 2007

  • Mucopolysaccharidosis Type I: Laronidase (Aldurazyme) approved in 2006

  • Mucopolysaccharidosis Type II (Hunter Syndrome): Idursulfase (Elaprase) approved in 2007

  • Gaucher disease: Imiglucerase (Cerezyme) approved in 1998

ERT has brought significant benefits for systemic muscle weakness and visceral symptoms. However, there is a barrier called the blood-brain barrier. Because enzymes administered via intravenous drip have difficulty reaching the brain, their effect on central nervous system symptoms has been limited.

Next-Generation Treatment: Reaching the Brain

To overcome this limitation, new approaches are being developed.

  • Intrathecal ERT: Direct administration of enzymes around the spinal cord

  • Intracerebroventricular ERT: Direct administration of enzymes into the brain ventricles (e.g., Cerliponase alfa (Brineura) for Neuronal Ceroid Lipofuscinosis Type 2, approved in 2019)

  • Gene therapy: Delivering normal genes into the body to produce the proteins that should naturally be made

  • Nucleic acid medicine (antisense oligonucleotides): Adjusting how genes are read to produce functional proteins

In particular, gene therapy, by administering AAV vectors directly into the brain, holds promise for improving central nervous system symptoms that were difficult to address with ERT.

🔹 Spinal Muscular Atrophy (SMA): The Arrival of Three Therapeutic Agents

What is SMA?

Spinal Muscular Atrophy (SMA) is a hereditary disease in which motor neurons in the spinal cord are gradually lost, leading to systemic muscle weakness. It occurs in approximately 1 in 20,000 people.

In the most severe Type I, symptoms appear by around 6 months of age, and without treatment, most were considered to pass away by age 2.

The Arrival of Therapeutic Agents

Currently, three types of therapeutic agents are approved in Japan.

  • Nusinersen (Spinraza) — Approved in 2017, intrathecal injection, continuous administration every 4 months

  • Onasemnogene abeparvovec (Zolgensma) — Approved in 2020, intravenous injection, one-time only

  • Risdiplam (Evrysdi) — Approved in 2021, oral administration, daily intake

Evidence of Therapeutic Efficacy

Five-year follow-up data from 2024 reports that with risdiplam administration for children with Type I SMA, 91% survived and 59% were able to sit without support. Considering that this was a disease where patients could neither survive past the age of two nor sit up without treatment, this is a dramatic improvement.

💡 Expert Perspective

SMA has become a 'treatable disease.' The earlier treatment begins, the higher the efficacy, and if treatment can be started before the onset of symptoms, better motor function can be expected. Therefore, early detection through newborn mass screening is extremely important.

🔹 Duchenne Muscular Dystrophy (DMD) — Exon Skipping Therapy

What is DMD?

Duchenne muscular dystrophy (DMD) is the most frequent hereditary muscle disease, occurring in approximately 1 in 5,000 boys. Due to a mutation in the gene that produces the protein dystrophin, muscle strength gradually declines, and walking becomes difficult around the age of 10.

What is Exon Skipping Therapy?

Genes are composed of multiple segments called 'exons.' In DMD, a portion of the gene is missing, preventing the production of normal protein.

'Exon skipping therapy' is a treatment method that 'skips over' the segment adjacent to the missing part, allowing the production of a slightly shorter but functional protein.

Therapeutic drugs approved in Japan

viltolarsen (Viltepso) — Approved in 2020

Developed jointly by the National Center of Neurology and Psychiatry (NCNP) and NS Pharma, this is a nucleic acid medicine originating from Japan. It skips exon 53 and is indicated for approximately 8–10% of DMD patients.

In 2025, it was reported that clinical trials for golodirsen, which skips exon 44, succeeded for the first time in the world in restoring dystrophin expression to over 20% of normal levels.

💡 Key Points of Treatment

Whether a patient is a candidate for exon skipping therapy depends on their genetic mutation pattern. The first step toward treatment is to identify the mutation through genetic testing.

🔹 AADC Deficiency — From Bedridden to Walker-Assisted Walking

What is AADC Deficiency?

Aromatic L-amino acid decarboxylase (AADC) deficiency is an extremely rare hereditary disease in which the enzymes necessary to produce neurotransmitters such as dopamine and serotonin do not function. Approximately 140 cases have been diagnosed worldwide, and about 8 in Japan.

In severe cases, symptoms appear in early infancy, including oculogyric crises and generalized tonic seizures, and most patients remain bedridden for life.

Achievements in Gene Therapy

Professor Takanori Yamagata and his team at Jichi Medical University have been conducting gene therapy using AAV vectors via stereotactic brain surgery since 2015.

Motor function improved in all six patients who received the treatment. Reports include cases where patients who were bedridden due to severe symptoms became able to walk with a walker, and cases where patients with intermediate symptoms progressed from needing assisted walking to being able to ride a bicycle. Additionally, seizures causing generalized tonicity have disappeared, and improvements in cognitive function have also been confirmed.

Gene therapy drugs for AADC deficiency (Upstaza / Kebilidi) were approved in Europe in 2022 and in the United States in 2024.

🔹 Tuberous Sclerosis Complex: Everolimus, Which Is Also Effective for Epilepsy

What is Tuberous Sclerosis Complex?

Tuberous sclerosis complex is a hereditary disorder caused by abnormalities in the TSC1 or TSC2 genes, leading to the development of various tumors (hamartomas) throughout the body. 84% of patients have comorbid epilepsy, and 70% of those cases are drug-resistant.

The Advent of the mTOR Inhibitor Everolimus

Everolimus (Afinitor) is the first therapeutic drug to act directly on the cause of tuberous sclerosis complex.

  • 2012: Approved for subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma

  • 2019: Indication expanded for focal onset seizures in epilepsy

In international joint clinical trials, 40% of patients in the high-dose everolimus group experienced a reduction in epileptic seizures of 50% or more (compared to 15% in the placebo group).

The addition of options other than anti-epileptic drugs as agents with the effect of 'reducing epilepsy' is a major advancement.

🔹 Early Detection is Key: Expansion of Newborn Mass Screening

Why Early Detection is Important

What these therapeutic drugs have in common is that 'the earlier treatment is started, the higher the efficacy.'

In SMA in particular, motor neurons lost after the onset of the disease do not recover, so starting treatment before onset can lead to development close to that of a healthy child.

Expansion of Newborn Mass Screening

Currently, newborn mass screening tests covering 20 diseases are being conducted nationwide in Japan.

In 2023, the Children and Families Agency announced a policy to add spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) as two new target diseases, and demonstration projects have been underway nationwide since 2024.

In addition, for lysosomal storage diseases (such as Pompe disease, mucopolysaccharidosis type I and II, etc.), testing is now available as an expanded newborn screening in some local governments.

Expectations for the Expansion of Mass Screening

The diseases that can be detected through newborn mass screening are limited to only a small fraction of the thousands of existing genetic disorders.

However, the diseases selected for screening are those that meet the following criteria:

  • They are serious diseasesthat

  • The prognosis improves if treatment is started earlythat

  • A highly reliable testing methodhas been established that

In other words, 'diseases that can be saved if found' are prioritized.

Diseases like SMA and SCID have been newly added to screening targets due to the emergence of effective treatments. It is hoped that the target diseases will continue to expand as treatment methods advance.

Currently, the reality is that there are differences in the diseases covered by screening depending on the local government. It is hoped that the system will be developed nationwide so that all babies can receive the same tests at public expense.

💡 To Parents/Guardians

Please check with the medical institution where you plan to give birth or your local government to see if expanded newborn screening is being conducted in your area. 'Early detection and early treatment' have the potential to significantly change your child's future.

🔹 New Challenges Brought by Advances in Treatment

New questions arising from being able to 'treat'

The emergence of treatment methods is a great hope, but at the same time, it also creates new challenges.

Long-term efficacy and safety

Many of these therapeutic drugs have only been approved for a few years. There is not yet sufficient data on their long-term efficacy and safety over 10 or 20 years. How the children who received treatment will live as adults will become clear in the future.

New medical needs after treatment

For example, in SMA, while early treatment significantly improves motor function, orthopedic issues such as scoliosis and joint contractures, as well as swallowing and speech problems that were not previously seen, are now receiving attention. Treatment goals are shifting from 'saving lives' to 'improving quality of life'.

Access to treatment and costs

Some gene therapy drugs cost over 100 million yen per dose. While insurance coverage reduces the burden on patients, the impact on the overall medical system cannot be ignored. Furthermore, facilities capable of providing specialized treatment are limited, and regional disparities remain a challenge.

The Importance of Multidisciplinary Treatment at Specialized Facilities

These new treatments are not simply a matter of administering a drug.

  • Accurate diagnosis and assessment of eligibility before treatment

  • Monitoring for side effects during treatment

  • Post-treatment rehabilitation and developmental support

  • Collaboration with multiple departments such as orthopedics, pulmonology, and cardiology

  • Genetic counseling and family support

Such multidisciplinary team medical care is essential.

In addition, by carefully tracking the progress of each patient and accumulating data, better treatment methods and support systems can be established. Cooperation with patient registry systems and participation in clinical research are also significant for the next generation of patients.

💡 Expert Perspective

Being able to 'treat' is not the goal, but a new beginning. To ensure that children who have received treatment can grow up healthily and play an active role in society, there is a need to build long-term support systems that integrate medical care, welfare, and education.

🔹 Summary: Toward an Era of 'Treatability'

  • The advent of enzyme replacement therapy (ERT) has made it possible to treat systemic symptoms such as those in lysosomal storage diseases

  • With the emergence of gene therapy and nucleic acid medicine, pediatric neurological disorders once considered 'untreatable' are entering an era where they can be treated

  • For SMA, three types of therapeutic drugs have been approved, and early treatment is improving motor function in many children

  • Exon skipping therapy for DMD and gene therapy for the brain in AADC deficiency are yielding results

  • For tuberous sclerosis, mTOR inhibitors have shown efficacy not only for tumors but also for epilepsy

  • Since early detection and early treatment maximize effectiveness, nationwide expansion of newborn mass screening is expected

  • On the other hand, challenges remain, such as verifying long-term efficacy and safety, and addressing new medical needs that arise after treatment

  • Multidisciplinary treatment at specialized facilities and the accumulation of evidence will become increasingly important in the future.

You might think, 'It's a rare disease, so it doesn't concern me,' but the progress in these treatments holds the potential to be applied to other neurological disorders in the future.

As a pediatric neurologist, I hope that parents will also become aware of this era filled with hope.

🔹 References and Materials

Children's Brain Lab | Pediatric Neurologist's Paper Notes

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