top of page

The Real-World Treatment Gap in Metachromatic Leukodystrophy: Why Children Need Options Beyond Gene Therapy (17 August 2026)

  • Release Tx
  • 2 days ago
  • 10 min read

When gene therapy for metachromatic leukodystrophy (MLD) was approved in Europe in 2020, followed by approval in the United States in 2024, it offered affected families something they had never had access to before: a disease-modifying treatment for this devastating form of childhood dementia. For the first time, it showed that the course of MLD could be meaningfully altered when treatment is delivered early enough.

 

In real-world practice, however, early intervention remains one of the most difficult conditions to achieve. In MLD, the central challenge is not only the speed of disease progression, but also the narrowness of the treatment window. Gene therapy has shown what may be possible when children are treated before substantial neurological damage has occurred. But it has also highlighted how much must fall into place for that possibility to become tangible for families: early diagnosis, timely referral, confirmation that the child is still eligible for treatment, payer approval, manufacturing and access to a qualified treatment centre. 

 

For most families, these conditions still do not align in time, a gap that defines the next challenge in MLD: developing treatment approaches that can meet the disease as it is encountered in practice, not only as it appears in the narrowest window of therapeutic opportunity. For children with MLD, the need is not simply for more innovation, but for options that reflect the urgency, complexity and clinical reality of the disease.  


Understanding MLD: Why time is critical


MLD is a rare, inherited and fatal neurodegenerative disorder, affecting approximately 1.6 in every 100,000 children born globally each year.[1] It is one of the most common forms of childhood dementia and typically claims young lives between the ages of five and eight.[2] MLD is caused by mutations in the arylsulfatase A (ARSA) gene, leading to a deficiency in the ARSA enzyme. As a result, toxic sulfatides accumulate in the central and peripheral nervous systems, causing progressive demyelination, neurocognitive decline and premature death.[3]


The disease manifests in three main subtypes, (i) late-infantile, (ii) juvenile and (iii) adult, classified by age of onset. The late-infantile form (LI-MLD) is the most aggressive and common, accounting for up to 60% of cases.[4] It typically strikes children under 30 months, who have only just begun to walk or speak. Early symptoms are subtle and non-specific: a toddler may stumble, lose motor coordination, or struggle with swallowing. Because children with LI-MLD are so young when symptoms first appear, the earliest changes can be difficult for families to recognise as signs of a serious neurological disorder. Even once medical advice is sought, MLD is so rare that it may not be among the first conditions considered, particularly in general paediatric settings. As a result, diagnosis can be delayed by months or even years.[5] In too many cases, the window for meaningful intervention has already begun to close by the time a diagnosis is made.


Despite the severity of MLD, treatment options remain extremely limited. Atidarsagene autotemcel, marketed as Libmeldy® in Europe and Lenmeldy® in the United States, is the only approved disease-modifying therapy for MLD and represents a major advance for children who can receive it early enough. It is an ex vivo autologous haematopoietic stem cell gene therapy indicated for pre-symptomatic children with LI-MLD and early juvenile MLD (EJ-MLD, characterised by symptom onset between 30 months and 6 years of age), as well as early-symptomatic children with EJ-MLD.


Its impact, however, depends on a narrow set of conditions that are often difficult to achieve in practice. Most children are diagnosed only after symptoms have begun, when treatment may no longer be available to them, or through family testing following the death of an affected sibling.[6] Earlier diagnosis through newborn screening could help identify children before symptoms appear, but MLD is not yet included in newborn screening programmes in most countries. Although momentum is building in Europe, the United States and West Asia, adoption remains uneven and gradual; to date, Norway is the first and only country to have introduced nationwide newborn screening for MLD.[7]


Even when MLD is diagnosed before symptoms appear, the treatment pathway can involve multiple time-sensitive steps, including referral, payer approval, cell collection, ex vivo processing, infusion and the time required for ARSA levels to reconstitute after treatment. Autologous cell collection and ex vivo gene therapy processing take approximately two months, while onset of therapeutic effect has been reported to occur three to six months after treatment.[8] In UK NHS case studies of two pre-symptomatic children with LI-MLD, the time from referral to Libmeldy infusion was 97 and 113 days, respectively.[9] Taken together, these timelines mean that the interval from referral to post-treatment ARSA reconstitution may approach ten months in some cases, a clinically significant period in a disease that can progress rapidly in early childhood.


The treatment process also reflects the complexity of autologous gene therapy. Children must undergo myeloablative conditioning before infusion and the therapy involves permanent genetic modification. These considerations do not diminish the importance of Libmeldy/Lenmeldy as a landmark therapy, but they do help explain why additional approaches are still needed: options that may be faster to deploy, easier to scale, reversible or redosable and accessible through a broader range of qualified clinical centres.

For most families, supportive care remains the only available option today. These interventions can help manage symptoms and preserve comfort, but they do not slow down or alter the course of the disease.[10] Once symptoms begin, MLD can progress rapidly. Within months to years, children may lose the ability to move, eat, speak, see and hear, while experiencing escalating seizures, respiratory complications and severe pain. Without disease-modifying intervention, LI-MLD is associated with particularly poor survival. One systematic review reported 10-year survival from symptom onset of 40% in one LI-MLD cohort, while another analysis found no LI-MLD survivors at 10 years from symptom onset.[11] 


The burden on families is profound. Parents often become full-time carers, with care for a child with LI-MLD exceeding 100 hours per week in some cases.[12] Late-stage care costs can reach EUR 9,600 per month, which are directed towards supportive measures that cannot change the trajectory of the disease.[13] Even as families do everything within their power to manage symptoms and preserve comfort, they too often face the relentless anticipatory grief of watching their child decline without hope of recovery.


The Myo-P4®: Reimagining Enzyme Replacement Therapy for the Brain


Enzyme replacement therapy (ERT) is one of the most direct disease-specific approaches for lysosomal storage disorders such as MLD. For these disorders, ERT is designed to deliver a functional recombinant counterpart of the deficient enzyme, usually via intravenous, intrathecal or intracerebroventricular administration.[14] In MLD, where the disease is driven by deficiency of the ARSA enzyme, the therapeutic goal is to replace the missing enzyme activity with functional recombinant ARSA. In principle, this makes ERT relevant beyond the narrow pre-symptomatic window, including for children who are diagnosed after symptoms have already begun.


The challenge, however, is delivery. ARSA must reach the right tissues, at sufficient levels and for long enough to make a meaningful difference in the central and peripheral nervous systems. As a treatment modality, ERT offers certain important advantages over gene therapy, including rapid onset of action, controlled dosing and the possibility of discontinuing treatment if needed.[15] Yet conventional ERT also faces important limitations, particularly for diseases affecting the central nervous system (CNS). Systemic delivery is constrained by the blood-brain barrier, which prevents most large molecules, including recombinant enzymes, from entering the brain in therapeutically meaningful concentrations. CNS-directed approaches, such as intrathecal or intracerebroventricular administration, can bring the enzyme closer to the site of disease, but they do not necessarily ensure sustained or widespread penetration into the brain parenchyma. Because dosing is intermittent, enzyme levels rise and fall between administrations, creating peak-trough swings that make it difficult to maintain stable therapeutic activity in the CNS. Repeated administration can also be invasive, especially when treatment is delivered directly into the cerebrospinal fluid.

 

These challenges have shaped the development of ERT for MLD. TAK-611, an intrathecally administered recombinant human ARSA therapy developed by Takeda, did not meet its primary efficacy endpoints in a Phase II study in 2023, although enrolled participants continue to receive treatment on compassionate-use grounds.[16] Its continued use underscores the persistent treatment gap in MLD, particularly for children who are not reached by gene therapy in time. More recently, engineered ARSA variants such as SuPerTurbo-ASA from the University of Bonn have shown promising preclinical results, including efforts to prolong enzyme half-life, improve sulfatide catalysis and enhance transport across the blood-brain barrier.[17] Together, these programmes reinforce the scientific rationale for ERT in MLD. They also highlight the central delivery challenge that remains: how to achieve durable, widespread and stable ARSA activity in the CNS without repeated invasive administration.


At Release Therapeutics, we are approaching this challenge in a different way, through encapsulated cell technology (ECT). ECT involves immobilising genetically engineered, living cells capable of producing therapeutic molecules within a semi-permeable membrane, enabling the molecules to diffuse into the target tissues while protecting the encapsulated cells from the host’s immune system. Cells are either encapsulated within microcapsules (sub-millimetre in size, encapsulating a few thousand cells), or macrocapsules (typically centimetre-scale devices, encapsulating millions of cells).[18] The semi-permeable membrane enables the outward diffusion of the therapeutic molecules, while also allowing the influx of oxygen and nutrients and protecting the encapsulated cells from the host's immune system. A key advantage of ECT is its ability to deliver sustained levels of therapeutics for long periods of time, without the need for repeat administration, making it a highly promising therapeutic approach for applications in the CNS.[19] 


This is the technology underpinning the Myo-P4, Release Therapeutics’ lead product candidate in MLD. Rather than administering ARSA through repeated injections or infusions, the Myo-P4 is intended to create a sustained local source of enzyme production for long-term delivery of ARSA directly within the CNS.


From Enzyme Replacement to Sustained CNS Delivery


For ECT to be viable in the brain, three elements need to work together:


  1. A cell source capable of long-term survival and therapeutic protein secretion;

  2. A device architecture that supports diffusion and immunoisolation; and

  3. An implantation strategy that enables sustained delivery while keeping the system controllable, retrievable and replaceable over time.


The Myo-P4 uses a proprietary immortalised human myoblast (IHM) cell line genetically engineered to produce ARSA. Myoblasts are muscle progenitor cells and are able to survive, proliferate and secrete proteins under hypoxic and metabolically restrictive conditions, making them particularly well suited for long-term intracerebral implantation where oxygen and nutrient availability are inherently limited. In fact, Release Therapeutics’ IHM cell line represents the first well-characterised, human-origin cell line specifically engineered to standardise cell macroencapsulation for clinical use.[20] The choice of a human allogeneic cell source reduces translational and immunological risk compared with xenogeneic approaches, such as Baby Hamster Kidney (BHK) cells, which are less well-adapted to long-term survival in a confined device. Based on our preliminary in vivo experiments with the technology, the IHMs are expected to enable continuous ARSA delivery beyond the blood-brain barrier over periods of at least 10 months, after which the implant is designed to be replaced with a new one to maintain therapeutic effect.21   


At the same time, the therapeutic potential of the IHM cell line depends on an encapsulation environment that can preserve cell viability while permitting efficient molecular exchange. In the Myo-P4, that environment is provided by the Myo-Pod, a proprietary ultra-compact and biocompatible encapsulation device designed to enable outward diffusion of therapeutic proteins, inward diffusion of oxygen and nutrients, and immunoisolation of the encapsulated cells.[21] This balance between protection and exchange has long been recognised as the “Achilles’ heel” of ECT and is precisely what the Myo-Pod was designed to address.[22] By using macroencapsulation rather than microencapsulation, the Myo-Pod also provides a defined, retrievable implant format that can support larger cell populations and more controlled therapeutic protein delivery, which is particularly important for applications in the paediatric brain.19


The Myo-Pod’s ultra-compact, retrievable architecture is well suited to subdural implantation, positioning ARSA-secreting cells close to the CNS while keeping the implant physically accessible for retrieval. The implantation procedure is expected to be a localised neurosurgical intervention lasting a few hours, involving small burr-hole openings to insert the implant, with recovery anticipated to take only a few days. The approach is intended to build on neurosurgical approaches already familiar in paediatric practice, such as the placement of Ommaya reservoirs for children with brain tumours and haematological malignancies.[23]


The preclinical evidence generated to date supports the rationale for our integrated cell-device approach. In ARSA-knockout mouse models of MLD, subcutaneous implantation of the integrated product reduced sulfatide accumulation and decreased neuroinflammatory markers in the brain and spinal cord, providing early proof-of-concept that ARSA secreted from encapsulated cells could have disease-relevant biological effects in CNS tissues.[24]

The latest evidence comes from an unpublished pilot non-human primate (NHP) study of the Myo-P4. In this study, two NHPs received three devices each by subural implantation and were followed for five months. The procedure demonstrated surgical feasibility and good tolerability over the implantation period. At explant, encapsulated cells were recovered, and ARSA activity was detected in the cerebrospinal fluid and brain tissue, with evidence of enzyme distribution and uptake in the CNS, including the spinal cord and brain parenchyma.


Taken together, these studies provide an important preclinical foundation for the Myo-P4 programme and suggest that encapsulated ARSA-secreting IHMs can remain viable after implantation and deliver biologically active enzyme to relevant CNS tissues over extended periods. The next step is to translate this foundation into a clinical-ready development package, to support progression towards clinical evaluation of the Myo-P4 in children with MLD.  


Expanding What is Possible in MLD


The approval of gene therapy changed the outlook for MLD by showing that disease modification is possible when treatment is early enough. But for too many children, that window remains difficult to reach. This is why additional therapeutic approaches are still needed. The next step in MLD is not simply to develop more treatments for the narrowest ideal scenario, but to build options that reflect how the disease is encountered in practice: urgently, unevenly and often after symptoms have already begun.


The Myo-P4 is being developed with that reality in mind. By combining enzyme replacement therapy with encapsulated cell technology, Release Therapeutics aims to create a sustained, local and replaceable approach to ARSA delivery in the CNS, without relying on permanent genetic modification or repeated enzyme administration.


For children with MLD and their families, the need is clear. Gene therapy has provided an important first disease-modifying option. The task now is to build on that progress with approaches that can broaden access, extend therapeutic possibility and bring treatment closer to the clinical reality of MLD.

 

References

 

 
 
 

Comments

bottom of page