TY - JOUR
T1 - Preclinical studies in Krabbe disease
T2 - A model for the investigation of novel combination therapies for lysosomal storage diseases
AU - Heller, Gregory
AU - Bradbury, Allison M.
AU - Sands, Mark S.
AU - Bongarzone, Ernesto R.
N1 - Funding Information:
Funding: pre-doctoral NRSA fellowship from the NIH (F30HD103447) to G.H.; NIH (R01 NS065808, R01NS127403), Legacy of Angels Foundation, and the European Leukodystrophy Association to E.R.B.; NIH (NICHD) R00HD096115 to A.M.B.; NIH (RO1NS100779) to M.S. G.H. wrote the manuscript. G.H. A.M.B. M.S.S. and E.R.B. contributed equally to reviewing, editing, and final formatting. All authors read and approved the manuscript. E.R.B. is a consultant for Lysosomal Therapeutics Inc. and Gain Therapeutics. Neither entity provided support in the form of salaries for any listed author nor played additional roles in the design, data collection and analysis, decision to publish, or preparation of this manuscript. A.M.B. is a beneficiary of a licensing agreement with Axovant Gene Therapies (royalties), has received income from Neurogene (consulting and honorarium), and is an inventor on a patent application (Gray SJ, Lykken E, Vite CH, Bradbury AM. Optimized GALC Genes and Expression Cassettes and Their Use. PCT/US2019/067727). G.H. and M.S.S. report no conflicts of interest.
Funding Information:
Funding: pre-doctoral NRSA fellowship from the NIH ( F30HD103447 ) to G.H.; NIH ( R01 NS065808 , R01NS127403 ), Legacy of Angels Foundation , and the European Leukodystrophy Association to E.R.B.; NIH ( NICHD ) R00HD096115 to A.M.B.; NIH ( RO1NS100779 ) to M.S.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/4
Y1 - 2023/1/4
N2 - Krabbe disease (KD) is a lysosomal storage disease (LSD) caused by mutations in the galc gene. There are over 50 monogenetic LSDs, which largely impede the normal development of children and often lead to premature death. At present, there are no cures for LSDs and the available treatments are generally insufficient, short acting, and not without co-morbidities or long-term side effects. The last 30 years have seen significant advances in our understanding of LSD pathology as well as treatment options. Two gene therapy-based clinical trials, NCT04693598 and NCT04771416, for KD were recently started based on those advances. This review will discuss how our knowledge of KD got to where it is today, focusing on preclinical investigations, and how what was discovered may prove beneficial for the treatment of other LSDs.
AB - Krabbe disease (KD) is a lysosomal storage disease (LSD) caused by mutations in the galc gene. There are over 50 monogenetic LSDs, which largely impede the normal development of children and often lead to premature death. At present, there are no cures for LSDs and the available treatments are generally insufficient, short acting, and not without co-morbidities or long-term side effects. The last 30 years have seen significant advances in our understanding of LSD pathology as well as treatment options. Two gene therapy-based clinical trials, NCT04693598 and NCT04771416, for KD were recently started based on those advances. This review will discuss how our knowledge of KD got to where it is today, focusing on preclinical investigations, and how what was discovered may prove beneficial for the treatment of other LSDs.
KW - Krabbe disease
KW - adeno-associated viral vectors
KW - demyelination
KW - lysosomal storage disease
KW - monogenetic diseases
KW - psychosine
KW - substrate reduction therapies
UR - http://www.scopus.com/inward/record.url?scp=85140052483&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2022.09.017
DO - 10.1016/j.ymthe.2022.09.017
M3 - Review article
C2 - 36196048
AN - SCOPUS:85140052483
SN - 1525-0016
VL - 31
SP - 7
EP - 23
JO - Molecular Therapy
JF - Molecular Therapy
IS - 1
ER -