Gene therapies in rare neurodegenerative diseases: a guide

What is a rare disease in the EU, and how does orphan designation work?

In the European Union a disease is considered rare if fewer than 5 in 10,000 people have it, and about 36 million people in the EU live with a rare disease. Most rare diseases – 80% – have identified genetic origins, and some of them appear at birth or in childhood, including spinal muscular atrophy and lysosomal storage disorders^[1].

The European Medicines Agency (EMA) reviews applications for orphan designation through its Committee for Orphan Medicinal Products (COMP), and the evaluation process takes a maximum of 90 days from validation. To qualify, a medicine must be intended for a disease that is life-threatening or chronically debilitating. The condition must affect no more than 5 in 10,000 people in the EU, and no satisfactory treatment may exist – or the medicine must offer significant benefit over the existing one. Since 2000, over 275 orphan medicines have been authorised in the EU^[1].

The three medicines described in this guide each hold orphan designation: Zolgensma since 19 June 2015, Spinraza since 2 April 2012, and Libmeldy since 13 April 2007^[2][3][4].

How do gene therapies and antisense oligonucleotides act on a faulty gene?

The two approaches are structurally different. A gene therapy delivers genetic material into the body, while an antisense oligonucleotide changes how an existing gene is read^[4][3].

Onasemnogene abeparvovec, the active substance in Zolgensma, contains a functional copy of the SMN1 gene. When injected it passes into the nerves and provides the correct gene to make enough of the protein needed for normal nerve function^[2]. In SMA the SMN protein is normally made from two genes, SMN1 and SMN2; patients lack SMN1, and SMN2 mostly produces a short protein that does not work as well as the full-length one. Nusinersen, the active substance in Spinraza, is a synthetic antisense oligonucleotide that enables SMN2 to produce full-length, functional protein^[3].

Libmeldy works differently again. Its active substance is the patient's own CD34+ stem cells. These cells are taken from bone marrow or blood. They are modified to carry a copy of the ARSA gene. A lentivirus, altered so that it cannot cause viral disease in humans, is used to insert the gene into the cells. After infusion, these cells make white blood cells that produce working arylsulfatase A (ARSA). This enzyme breaks down sulfatides^[4].

In SMA, the viral-vector approach – a single intravenous injection of adeno-associated virus 9 (AAV9) carrying the SMN1 gene – produced improvements in survival and motor function, and has become a template for gene therapy in neurodegenerative disease^[5].

How are these medicines given, and what happens around the infusion?

All three are given by infusion into a vein, but the preparation and the setting differ.

Medicine	Active substance	How it is given	Setting	Before and after
Zolgensma	onasemnogene abeparvovec	one infusion lasting about 1 hour	clinic or hospital, doctor experienced in SMA	liver and blood tests before and after; corticosteroid medicines to reduce the risk of side effects[2]
Spinraza	nusinersen	intrathecal injection into the lower back; the patient may need to be sedated first	doctor experienced in SMA; given by a doctor or nurse experienced in the procedure	started as soon as possible after diagnosis and continued for as long as the patient benefits[3]
Libmeldy	autologous CD34+ cells encoding ARSA gene	single infusion; dose depends on body weight	specialist transplant centre	busulfan given a few days earlier as conditioning to clear existing bone marrow cells; other medicines given beforehand to reduce the risk of reactions[4]

Libmeldy can only be given to the patient whose cells were used to make it^[4]. Zolgensma is given once, and the infusion should take place under the supervision of a doctor experienced in managing spinal muscular atrophy^[2].

What did the studies show before these medicines were authorised?

The evidence base for each medicine came from a main study in a small number of children, which is typical for a rare disease^[2][3][4].

Onasemnogene abeparvovec: survival without a permanent ventilator

A main study showed that Zolgensma reduces the need for artificial ventilation in babies with spinal muscular atrophy. Of 22 babies given the medicine, 20 were alive and breathing without a permanent ventilator after 14 months, whereas normally only a quarter of untreated patients would survive without needing a ventilator. After 18 months, 14 of the 22 could sit unaided for at least 30 seconds – a milestone never achieved in untreated babies with severe forms of the disease^[2].

Nusinersen: movement milestones versus placebo

One main study involved 121 babies with SMA, of an average age of 7 months. After one year of treatment, 51% of babies receiving Spinraza (37 out of 73) showed progress in developing head control, rolling, sitting, crawling, standing and walking, while no similar progress was seen in any baby who received placebo. Most babies treated with Spinraza survived longer and needed breathing support later than those given placebo. A second study in children whose SMA was less severe and diagnosed later (average age 3 years) found improvement in movement in 57% of children receiving Spinraza compared with 26% on placebo after 15 months^[3].

Libmeldy: motor function scores compared with untreated children

The main study involved 20 children with late infantile or early juvenile MLD. ARSA activity increased in all children within 3 months of treatment. Levels reached above or within the range for healthy children. After 2 years, the overall Gross Motor Function Measure score was 72.5 in the late infantile group. This score ranges from 0 to 100. It measures a developing child's ability to make normal movements such as crawling, standing and walking. In records of similar untreated children, the score was 7.4. In early juvenile MLD the average score was 76.5 against 36.3 in previous untreated cases. Benefit was greatest in children who had not yet developed symptoms. Benefit seemed to be lost in those who could no longer walk independently or had developed mental deterioration. Evidence showed continuing benefit on follow-up for up to 8 years^[4].

What does a gene therapy trial measure at each phase?

Phase 1 trials assess the safety of a treatment, how it behaves in the body and its chemical effects, but not its effect on symptoms^[6].

That distinction matters for how you read early results. In a Phase 1 trial of the antisense oligonucleotide BIIB080 in Alzheimer's disease, 46 patients took part – 34 received the drug and 12 a placebo, delivered into the cerebrospinal fluid. None of the participants had serious side effects, and those who received the highest dose showed over 50% reduction in tau levels after 24 weeks. The trial leader stated that further research is needed to understand the extent to which the drug can slow progression of physical symptoms^[6].

BIIB080 is an antisense oligonucleotide made of RNA pieces with sequences complementary to the messenger RNAs that act as templates for the MAPT gene to be turned into tau protein. When the sequences match, the messenger RNA is inactivated and destroyed by the cell, so less protein is made while the gene itself is not affected^[6].

Why do single-dose gene therapies need long-term follow-up?

A one-time treatment cannot be stopped or adjusted in the same way as a medicine taken daily, so safety is tracked after authorisation. The company marketing Zolgensma will conduct a study of the medicine's safety and effectiveness in the long term, and data on its use are continuously monitored. Zolgensma was originally given conditional authorisation because more evidence was expected, and the authorisation was switched to full authorisation once the company supplied the additional information^[2].

For Libmeldy, the effects are expected to be long-lasting, and continuing benefit was observed on follow-up for up to 8 years^[4]. The company marketing Zolgensma also provides educational materials to caregivers on how to use the medicine safely, the risks associated with it, and how to identify and report side effects^[2].

Which side effects are patients monitored for?

For Zolgensma, the most common side effects are raised liver enzymes, liver injury (hepatotoxicity), low levels of blood platelets (thrombocytopenia), raised troponin levels (a measure indicating damage to the heart muscle), fever and vomiting. Raised liver enzymes, the most common side effect in the study, required treatment with a steroid, and the side effects were considered manageable^[2].

For Spinraza, the most common side effects – affecting more than 1 in 10 people – include headache, back pain and vomiting, and these are thought to be caused by the injections into the spine used to give the medicine. In babies, some side effects could not be assessed because the babies could not communicate them^[3].

For Libmeldy, the most common side effect – which may affect more than 1 in 10 people – is the development of antibodies to ARSA^[4].

How are gene therapy trials for neurodegenerative diseases designed?

The FDA guidance on human gene therapy for neurodegenerative diseases covers study design, study population, dose selection, safety considerations, study endpoints, follow-up duration and patient experience, and describes expedited programmes for these products. It applies to gene therapy products for neurodegenerative diseases affecting both adult and paediatric patients, a heterogeneous group of disorders characterised by progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. In the United States this guidance describes the agency's current thinking and is not binding; it is not a statement of European requirements^[7].

The scientific rationale for these programmes rests on viral vectors that can deliver genes throughout the central nervous system. It also rests on genome-engineering tools that can manipulate disease pathways. The field also carries the memory of a serious setback. More than two decades ago a relatively healthy 18-year-old volunteer in a gene therapy trial died, likely because of a fatal immune response triggered by adenovirus vectors. Subsequent work focused on mitigating viral vector-induced immune activation^[5].

What other gene-based approaches are being studied in neurodegenerative disease?

In amyotrophic lateral sclerosis (ALS), the most common cause is a variant in the C9orf72 gene, present in around 10% of patients. The disease-causing variant contains an expansion of a six-base-pair sequence repeated many times, and the same variant is implicated in frontotemporal dementia (FTD)^[8].

RNA molecules containing the repeat build up in the cell. This causes large quantities of non-functional protein to be made. This build-up to toxic levels is believed to be the main cause of disease symptoms. One research direction uses antisense oligonucleotides. These are small nucleotide sequences that bind to C9orf72 mRNA molecules containing the repeat. They cause the cell to destroy them. This approach has shown promise in the laboratory. A clinical trial is now taking place. Newer research found that the small proteins made when the repeats were transcribed and translated impair the activity of EXOSC10. EXOSC10 is a key protein in the RNA exosome complex responsible for degrading RNA molecules. This may explain why toxic RNA and proteins accumulate^[8].

Samples from people with ALS and mouse models also showed that healthy C9orf72 protein has an immunological function, and that cells from patients with the expanded variant and FTD showed a heightened immune response. These are laboratory and animal findings that identify targets for potential therapies, not treatments available to patients^[8].

How can a patient or caregiver find a trial and take part?

If you are considering participation, the first practical step is to ask the treating specialist whether any trial is open for the specific genetic diagnosis. Eligibility in the studies described here depended on the gene involved and the disease form. For Libmeldy, eligibility also depended on whether symptoms had already appeared^[4]. Zolgensma is intended for patients with inherited mutations affecting SMN1. These patients have either been diagnosed with SMA type 1 or have up to 3 copies of SMN2^[2]. Libmeldy is used in children with MLD who have mutations in the ARSA gene. It is used in late infantile or early juvenile forms before symptoms appear. It is also used in early juvenile MLD with initial symptoms in children who can still walk independently and have not developed mental deterioration^[4].

Trials recruiting in Europe can be searched on clinicaltrials.eu. Before consenting, ask what the trial will measure – in the Phase 1 BIIB080 study the primary purpose was safety and effects in the body, not symptom change – and what follow-up will be required of you^[6]. For treatments already authorised, the package leaflet lists the full set of restrictions and side effects, and your doctor or pharmacist can explain them^[2][4].

When should a patient or caregiver seek advice from a doctor or pharmacist?

Contact the treating team if, after a Zolgensma infusion, your child develops fever, vomiting or unusual bruising or bleeding, because fever and vomiting are listed side effects and low blood platelets are among the recognised risks^[2]. After Spinraza, report headache, back pain or vomiting, which are the most common side effects and are thought to be related to the spinal injections^[3]. After Libmeldy, ask about monitoring for antibodies to ARSA, the most common side effect^[4]. For any medicine, side effects can be reported through the national reporting system described in the package leaflet^[2].

Summary

Gene-based medicines for rare neurodegenerative diseases are authorised on the basis of small main studies. The numbers are specific: 22 babies in the onasemnogene abeparvovec study. For nusinersen, 121 babies plus a second paediatric study. For Libmeldy, 20 children^[2][3][4].

Three practical points follow. Check the eligibility criteria against the actual genetic result, since the authorised indications are defined by gene, disease form and, for MLD, by symptom stage^[4][2]. Ask what a trial measures at its phase, because Phase 1 looks at safety and effects in the body rather than symptoms^[6]. And plan for follow-up, since long-term safety and effectiveness data are collected after authorisation for one-time treatments^[2].

This article is for information and education only and does not replace advice from your doctor, pharmacist or specialist treatment team.

1. [1] Orphan designation: Overview (accessed 2 June 2026) — https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview
2. [2] Zolgensma (accessed 2 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma
3. [3] Spinraza (accessed 2 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/spinraza
4. [4] Libmeldy (accessed 2 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/libmeldy
5. [5] Gene-based therapies for Neurodegenerative Diseases - PMC — PubMed Central (accessed 20.10.2026) — https://pmc.ncbi.nlm.nih.gov/articles/PMC8394447/
6. [6] Clinical trials show promise for first ‘gene silencing’ treatment for Alzheimer’s disease (accessed 2 June 2026) — https://www.genomicseducation.hee.nhs.uk/blog/clinical-trials-show-promise-for-first-gene-silencing-treatment-for-alzheimers-disease/
7. [7] Human Gene Therapy for Neurodegenerative Diseases; Guidance for Industry (accessed 2 June 2026) — https://www.fda.gov/media/144886/download
8. [8] Breakthrough in the battle against neurodegenerative disease (accessed 2 June 2026) — https://www.genomicseducation.hee.nhs.uk/blog/breakthrough-in-the-battle-against-neurodegenerative-disease/