Severe junctional epidermolysis bullosa (sJEB) is a rare genetic, often postpartum lethal epithelial disease that is predominantly caused by biallelic nonsense/premature termination codon (PTC) sequence variants in the LAMB3 gene [1]. LAMB3 gene encodes the β3 chain of the trimeric, hemidesmosomal skin anchor protein laminin 332. PTC mutations prevent the synthesis of full-length functional proteins, and truncated laminin ß3 (lamß3) prevents the formation of laminin 332, with devastating clinical manifestations. These include generalized blistering at birth, periorificial erosions around the mouth, eyes, and nares, significant loss of mucosal surfaces of inner organs, hoarse cry, cough and respiratory difficulties. Sepsis and general failure to thrive result in the demise of patients in early infancy [2]. The condition is currently incurable and would require long-term systemic correction. Artesunate is an FDA-approved, bioavailable small molecule drug for systemic treatment of malaria [3]. It is primarily effective in the blood compartment and can be administered intravenously or orally with minimal side effects. Artesunate is a derivative of artemisinin, a compound originally isolated from the plant Artemisia annua. Its mode of action primarily involves the generation of reactive oxygen species (ROS) within the malaria parasite Plasmodium. It is targeting the parasite’s haemoglobin digestion process inside red blood cells. The drug is activated by the iron present in the heme (from broken-down hemoglobin) and forms free radicals which damage the parasite’s proteins and lipids, leading to its death [4].

Targeted ribosome editing in yeast and human cells identified artesunate as an efficient enhancer of lamß3 protein translation [5–8]. Here, application of artesunate to both sJEB-LAMB3 HaCat model cells and to immortalized sJEB-LAMB3 patient keratinocytes revealed a significant increase of lamß3 protein after 4 days of treatment with 1 µM artesunate/0.01% DMSO in CnT Prime medium (Fig. 1). Thus, we describe the use of artesunate in a patient with sJEB, homozygous for a LAMB3PTC mutation. A girl of 3 months of age was presented to the clinic with the phenotype of sJEB. In addition to widespread chronic wounds, she had growth retardation, anemia, and repeating episodes of infections (i.e., respiratory infections, bacterial wound infections, candida infection in oral mucous membranes). Since birth, her wounds were treated with various wound dressings, that were adjusted to the local condition. In general, for this indication, no approved treatment is available. Therefore, the parents agreed to start the off-label treatment with artesunate.

Artesunate was administered initially in calendar week (cw) 39 2023 intravenously with a total amount of 3 mg q.d., then switched to an oral application with 10 mg daily (1 ml of 10 mg/ml oral suspension) and increased to 20 mg after 3 months and to 40 mg after 6 months (Table 1). Artesunate was well tolerated; side effects resulting from anemic episodes most likely due to iron deficiency and chronic disease were met with discontinuing treatment. Clinical response showed a mixed picture: During the first 5 months of treatment, no effect on wound healing (nates and flanks) was observed according to the treating physician’s assessment. An immunofluorescence (IF) investigation of patient skin was performed after these 5 months of treatment and showed only a marginal increase in expression of lamß3 protein (Fig. 2). However, respiratory complications improved with the start of oral administration (cw 41) and returned when oral treatment was paused during infectious episodes. From December 2023 to January 2024, artesunate was also administered topically (10 mg/ml) q.d. to the affected areas on the flanks with no signs of re-epithelialization (not shown). After 6 months, oral dosing was increased to 40 mg daily. After one week of treatment at this dosage, the patient’s wounds on the nates began to show gradual healing (Fig. 3). However, the patient´s general condition worsened, and she died in cw 19 2024.

Biochemical and in vitro evidence suggests that the specific binding of artesunate to ribosomal LP35 leads to stop codon readthrough in the premature termination stop codons of the LAMB3 gene. Here, a patient with s-JEB-LAMB3 was treated with intravenous, oral and topical artesunate to determine safety in neonates. Safety was acceptable, and in areas where artesunate had local access (oral cavity, perianal), positive clinical effects were reported by treating physicians and visually documented (Fig. 3). Other systemic treatments for s-JEB include aminoglycosides, such as gentamicin [9], and non-aminoglycosides, such as ataluren [10], to promote general ribosomal readthrough. Gentamicin is not available orally and treatment options are limited to pulsed, short-term intravenous applications due to nephrotoxic and ototoxic effects. Ataluren is available orally, but there are no safety studies on long-term use in EB of this compound. Both compounds are compromised by their lack of specificity, i.e. they are general PTC readthrough drugs that are unable to distinguish between PTC signals resulting from mutations and endogenous PTC signals that regulate the production of protein isoforms. Possible reasons why the clinical outcome in this patient could not be changed include: 1) Bioavailability of artesunate in the skin as opposed to the blood system. 2) The initiation and dosage of treatment, which probably preclude the timely accumulation of laminin ß3 protein in epithelial tissues. 3) Effects of prenatal loss of laminin ß3 [11] leading to immune dysregulation. Future studies that treat patients as early as possible to reduce the formation of large wounds and promote the formation of intact oral and intestinal mucosa, as well as strategies to develop artesunate derivatives with improved bioavailability, are warranted.