Lysosomal storage diseases are inborn errors of metabolism associated with over 50 causative monogenic loci. Nearly two thirds have prominent neuropathology, leading to developmental delay and regression, with subsequent neurodegeneration and early lethality. Hematopoietic stem cell transplant is a therapeutic option for a subset of these disorders, but significant hurdles exist involving timely diagnosis, as many disorders may have a therapeutic window of opportunity such that children need to receive treatment by a specific age or stage of disease. Compounding this are other issues including donor availability, significant potential morbidity and mortality, and overall issues of equity and access to medical care.
Using approaches pioneered for therapy of Severe Combined Immunodeficiency Syndromes involving transplant with exvivo, lentiviral-treated hematopoietic stem cells, academic and industry sponsored research have led to the recent FDA and EMA approval of atidarsagene autotemcel as a therapy for metachromatic leukodystrophy. The advent of this and related therapies has the potential to transform the patient outcomes of metachromatic leukodystrophy and multiple additional lysosomal storage diseases.

In this session we will provide an overview of the neuropathic lysosomal storage disorders, with a focus on those caused by defects in soluble enzymes, including the state of clinical practice addressing these conditions. Advancing novel treatments in these disorders will require pre-clinical diagnosis of the sort that can only be provided in a comprehensive way through public health based newborn screening. Advancing newborn screening of neuropathic lysosomal storage diseases from proof of principle screening technology to listing by the Secretary of Health and Human Services on the Recommended Uniform Screening Panel (RUSP), and subsequent adoption by the states will be covered using mucopolysaccharidosis type I as an example. The institutional and regulatory challenges of simultaneous progress in drug development and newborn screening initiatives will be presented. With the current and anticipated advances in newborn screening, transformative therapies with ex vivo gene altered autologous stem cell transplant have the potential to become a new and compelling standard of care for these disorders.

Approved treatments such as that for metachromatic leukodystrophy will be discussed as well as similar active trials in mucopolysaccharidosis type I, type II and type IIIA. Finally, the approach of stem cell gene therapy is not confined to lentiviral vectors but is also amenable to the use of targeted gene delivery with CRISPR-mediated techniques. The session concludes with an overview of pre-clinical model research in mucopolysaccharidosis type I involving autologous stem cell transplant with CRISPR-mediated ex vivo gene insertion in a safe harbor in the genome, which is being developed as a next generation platform approach to treating this class of disorders with gene altered stem cells.