Common hereditary lysosomal storage diseases - Emerging treatments

Enzyme replacement therapy

New types of enzyme replacement therapy are in development or are available. Olipudase alfa has been approved by the US Food and Drug Administration (FDA) for use in patients with Acid Sphingomyelinase Deficiency (ASMD) a rare lysosomal storage disease and has FDA breakthrough therapy designation for Niemann-Pick's disease type B. The European Medicines Agency (EMA) has approved olipudase alfa for Niemann-Pick's disease type A/B or type B. The FDA and EMA have both approved velmanase alfa as a long-term enzyme replacement therapy in adults, adolescents, and children with mild to moderate forms of alpha mannosidosis. It is used for treating non-neurological effects as it does not appear to reach the brain. Cerliponase alfa has also been approved by both the FDA and EMA for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2). In the UK it is only available under a managed access agreement.[171] The FDA has granted fast-track designation to tividenofusp alfa, an enzyme replacement therapy for the treatment of cognitive, behavioural, and physical symptoms in Hunter Syndrome (MPS II), with clinical trials ongoing. The therapy aims to reduce cerebrospinal heparan sulfate levels, implicated in Hunter Syndrome. Initial results showed improved biochemical markers associated with Hunter Syndrome, alongside improved qualitative clinician and carer scores.[172]

Gene therapy

Trials examining the use of iduronicrin genleukocel-T (autologous plasmablasts engineered to express laronidase, also known as alpha-L-iduronidase) are ongoing in patients with mucopolysaccharidosis (MPS) type 1 who have undergone allogeneic stem cell transplantation.[173] SIG-007, a form of gene therapy for Fabry disease, has been granted orphan drug status by the FDA. 4D-310, a gene therapy that delivers a functional alpha-galactosidase A gene to people with Fabry disease (using adeno-associated viral vectors), is under investigation.[174] Another gene therapy for Fabry disease, isaralgagene civaparvovec has been granted fast-track designation by the FDA. Gene therapy with autologous haematopoietic stem and progenitor cells modified to contain a copy of the gene that makes ARSA arylsulfatase A (atidarsagene autotemcel) has been approved in the US and Europe for the treatment of metachromatic leukodystrophy.

Chaperone therapy

While chaperone therapy is established in Fabry disease, trials are under way in Pompe disease.[175]

Arimoclomol

The FDA has approved arimoclomol (to be used in combination with miglustat) for the treatment of neurological symptoms associated with Niemann-Pick’s disease type C in children aged ≥2 years and adults; however, it was not approved by the EMA. Arimoclomol acts as a heat-shock protein inducer to target protein misfolding associated with Niemann-Pick’s disease type C. It showed slower disease progression in phase 2 and 3 randomised controlled trials.[176]

Levacetylleucine

Levacetylleucine has been approved by the FDA for treating neurological symptoms associated with Niemann-Pick’s disease type-C in children who weigh ≥15 kg and adults; however, it has not been approved by the EMA. It is a derivative of the amino acid leucine, and while the specific molecular target for Niemann-Pick’s disease type C is unknown, levacetylleucine enters metabolic pathways which improve adenosine triphosphate production, ultimately reducing the storage of unesterified cholesterol and sphingolipids implicated in Niemann-Pick’s disease type-C. Trial results showed improvements in neurological assessments including sitting, stance, and speech.[177]