The first gene therapy approach for MLC leukoencephalopathy, designated as an orphan drug

  • MLC leukoencephalopathy is a rare genetic disease characterized by megalencephaly, loss of motor functions, epilepsy, and moderate mental retardation.
  • The gene therapy approach designated as orphan drug has reduced the symptoms of MLC in the pre-clinical phase in model mice of the disease.
  • The development of this orphan drug has been co-led by the IDIBELL and UB-CIBERER research group led by Raúl Estévez and group led by Assumpció Bosch at the UAB.
  • The orphan drug designation offers incentives to continue the clinical research process with the ultimate goal of obtaining marketing authorization.
NdP medicamento huérfano MLC 191121_Imatge

The first gene therapy approach to treat megalencephalic leukoencephalopathy with subcortical cysts (MLC) has been designated as an orphan drug by the European Medicines Agency (EMA). Those responsible for the work have managed to reduce the symptoms of this rare disease in preclinical models.

The designation of this orphan drug, whose promoter is the Center for Biomedical Research in Network for Rare Diseases (CIBERER), has been the result of the research project led by the group of Raúl Estevez from CIBERER at the Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona (UB), together with the group led by Assumpció Bosch at the Autonomous University of Barcelona (UAB). Researchers linked to the Vall d’Hebron Research Institute (VHIR) and the Catalan Institution for Research and Advanced Studies (ICREA) have also participated in the project.

So far, there is only available supportive treatment and it doesn’t exist any curative therapy for patients affected by MLC, a monogenic disease characterized by megalencephaly, loss of motor functions, epilepsy, and moderate mental retardation that is caused by mutations in two different genes. “In most cases, the disease is caused by mutations in one of them, Mlc1,” explains Raúl Estévez, an expert in the molecular mechanisms of the disease.

In brain biopsies of patients with MLC, the accumulation of water in the form of vacuoles has been observed in myelin (the insulating layer that forms around the nerves) and in astrocytes (basic cells for the maintenance of neuronal function) that surround the blood vessels.

Those responsible for this work have been able to improve MLC disease in the preclinical phase using a mouse model with the inactivated Mlc1 gene. Researchers have prepared adeno-associated viruses that express Mlc1 and include the promoter for the GFAP protein, which allows expression of the corrected gene in MLC1-expressing cells. Subsequently, they have been injected into the subarachnoid space of the cerebellum of the mouse model as an effective route of administration.

“This research is the first therapeutic approach that has been developed for MLC and could also have implications for the treatment of other diseases that affect motor functions, such as ataxias,” says Assumpció Bosch, an expert in gene therapy.

Now, once the designation has been obtained, the drug must continue with the clinical research process to establish the safety, efficacy and quality profile, with the aim of finally obtaining the marketing authorization from the regulatory authorities.


About MLC leukodystrophy

MLC is a form of leukodystrophy characterized by childhood-onset macrocephaly, often with mild neurological symptoms at presentation (such as mild motor retardation), which worsen over time, leading to a gait disorder, falls, ataxia, spasticity, seizures of increasing frequency and intensity, and cognitive impairment. Brain MRI images show diffuse involvement and slight inflammation of the white matter, as well as subcortical cysts in the anterior temporal and frontoparietal regions.

The estimated prevalence of MLC in the European population is around 0.01 per 10,000 people and is considered an ultra-rare disease (defined as one that affects less than 1 in 2,000 people).


Benefits of Orphan Drug Designation

EMA designation as an orphan drug has advantages such as receiving a marketing authorization for ten years, in which similar products cannot be marketed. Also have free or reduced costs for scientific advice and protocol assistance, in addition to the exemption of payments for the designation. Finally, the entities that develop orphan drugs have access to specific subsidies from the European Union and from member state programs.



The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).

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