Long-Term Outcome of Gene Therapy for MLD and Prospective Newborn Screening: The Tübingen Experience

Background/Purpose: MLD is a lysosomal storage disorder caused by ARSA deficiency. Atidarsagene autotemcel (ARSA-cel, Libmeldy), an ex vivo autologous CD34+ hematopoietic stem cell gene therapy, was approved by EMA in 2020 to treat children with pre-symptomatic (PS) late infantile [LI], early juvenile [EJ] MLD, and EJ MLD with first symptoms without cognitive decline or loss of walking. As one of 5 qualified European treatment centers, we present clinical development long-term data and share our own treatment experience in Tübingen, including treatment of 2 patients identified by a newborn screening (NBS) pilot study.

Methods: The clinical trial program for ARSA-cel, conducted at SR-TIGET in Milan, included 39 patients with early-onset MLD (19 LI, 20 EJ) followed prospectively to assess safety and efficacy compared with a historical cohort of 43 early-onset MLD subjects (NHx). From 2021, a prospective MLD NBS pilot study using biochemical and genetic testing in DBS was initiated at the Screening Center in Hannover.

Results: Follow-up of 39 patients treated at SR-TIGET for up to 12 years (median 6.76 years, range 0.64–12.19) showed no treatment-related SAEs, no signs of insertional mutagenesis or replication-competent lentivirus to date. Over 95% (25/26) of PS patients retained the ability to walk at last follow-up and maintained normal or near-normal cognitive development. So far, from the NBS study, three cases have been identified and diagnosed, two of them were classified as EJ form and were treated with ARSA-cel at age 11 months.

Conclusion: Long-term data confirm the favorable safety profile and sustained efficacy of ARSA-cel in preventing severe motor and cognitive impairment in early-onset MLD patients, particularly in the presymptomatic phase underlining the importance of NBS to allow early diagnosis and treatment. Inclusion of MLD into the national NBS programs will enable treatment intervention with ARSA-cel for early onset MLD ensuring best possible outcomes.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
13 November 2023