December 2024 Research Spotlight:

FOCUS ON LYSOSOMAL DISEASES

The fourth edition of SPOTLIGHT highlights recent scientific publications on lysosomal diseases. Authors who have been speakers at WORLDSymposium are noted in bold.

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• α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial
  Harmatz P, Giugliani R, Martins AM, Hamazaki T, Kubo T, Kira R, Minami K, Ikeda T, Moriuchi H, Kawashima S, Takasao N, So S, Sonoda H, Hirato T, Tanizawa K, Schmidt M, Sato Y.
  Mol Ther. 2024 Mar 6;32(3):609-618. doi: 10.1016/j.ymthe.2024.01.009. Epub 2024 Jan 10. PMID: 38204164
• Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome
  Consiglieri G, Tucci F, De Pellegrin M, Guerrini B, Cattoni A, Risca G, Scarparo S, Sarzana M, Pontesilli S, Mellone R, Gasperini S, Galimberti S, Silvani P, Filisetti C, Darin S, Forni G, Miglietta S, Santi L, Facchini M, Corti A, Fumagalli F, Cicalese MP, Calbi V, Migliavacca M, Barzaghi F, Ferrua F, Gallo V, Recupero S, Canarutto D, Doglio M, Tedesco L, Volpi N, Rovelli A, la Marca G, Valsecchi MG, Zancan S, Ciceri F, Naldini L, Baldoli C, Parini R, Gentner B, Aiuti A, Bernardo ME.
  Sci Transl Med. 2024 May;16(745):eadi8214. doi: 10.1126/scitranslmed.adi8214. Epub 2024 May 1. PMID: 38691622
• Comparative dose effectiveness of intravenous and intrathecal AAV9.CB7.hIDS, RGX-121, in mucopolysaccharidosis type II mice
  Smith MC, Belur LR, Karlen AD, Erlanson O, Furcich J, Lund TC, Seelig D, Kitto KF, Fairbanks CA, Kim KH, Buss N, McIvor RS.
  Mol Ther Methods Clin Dev. 2024 Jan 30;32(1):101201. doi: 10.1016/j.omtm.2024.101201. eCollection 2024 Mar 14. PMID: 38374962
• Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease
  Mandolfo O, Liao A, Singh E, O’leary C, Holley RJ, Bigger BW.
  Hum Gene Ther. 2024 Apr;35(7-8):243-255. doi: 10.1089/hum.2023.002. Epub 2023 Aug 30. PMID: 37427450
• Genotype-phenotype findings in patients with mucopolysaccharidosis II from the Hunter Outcome Survey
  Muenzer J, Amartino H, Burton BK, Scarpa M, Tylki-Szymańska A, Audi J, Botha J, Fertek D, Merberg D, Natarajan M, Whiteman DAH, Giugliani R.
  Mol Genet Metab. 2024 Sep-Oct;143(1-2):108576. doi: 10.1016/j.ymgme.2024.108576. Epub 2024 Sep 10. PMID: 39303318
• Ability change across multiple domains in mucopolysaccharidosis (Sanfilippo syndrome) type IIIA
  Shapiro EG, Eisengart JB, Whiteman D, Whitley CB.
  Mol Genet Metab. 2024 Feb;141(2):108110. doi: 10.1016/j.ymgme.2023.108110. Epub 2023 Dec 15. PMID: 38151384
• Anakinra in Sanfilippo syndrome: a phase 1/2 trial
  Polgreen LE, Chen AH, Pak Y, Luzzi A, Morales Garval A, Acevedo J, Bitan G, Iacovino M, O’Neill C, Eisengart JB.
  Nat Med. 2024 Sep;30(9):2473-2479. doi: 10.1038/s41591-024-03079-3. Epub 2024 Jun 21. PMID: 38907160
• AAV gene replacement therapy for treating MPS IIIC: Facilitating bystander effects via EV-mRNA cargo
  Bobo TA, Robinson M, Tofade C, Sokolski-Papkov M, Nichols P, Vorobiov S, Fu H.
  J Extracell Vesicles. 2024 Jul;13(7):e12464. doi: 10.1002/jev2.12464. PMID: 38961538
• Evaluation of neuroretina following i.v. or intra-CSF AAV9 gene replacement in mice with MPS IIIA, a childhood dementia
  Beard H, Winner L, Shoubridge A, Parkinson-Lawrence E, Lau AA, Mubarokah SN, Lance TR, King B, Scott W, Snel MF, Trim PJ, Hemsley KM.
  CNS Neurosci Ther. 2024 Aug;30(8):e14919. doi: 10.1111/cns.14919. PMID: 39123298
• Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC
  Pan X, Caillon A, Fan S, Khan S, Tomatsu S, Pshezhetsky AV.
  Cells. 2024 May 20;13(10):877. doi: 10.3390/cells13100877. PMID: 38786099
• Implementation of newborn screening for mucopolysaccharidosis type IVA and long-term monitoring in Taiwan
  Lin HY, Lee CL, Chang YH, Tu YR, Lo YT, Wu JY, Niu DM, Liu MY, Liu HY, Chen HJ, Kao SM, Wang LY, Ho HJ, Chuang CK, Lin SP.
  Genet Med. 2024 Dec;26(12):101286. doi: 10.1016/j.gim.2024.101286. Epub 2024 Oct 4. PMID: 39375993
• Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice
  Herreño-Pachón AM, Sawamoto K, Stapleton M, Khan S, Piechnik M, Álvarez JV, Tomatsu S.
  Hum Gene Ther. 2024 Dec;35(23-24):955-968. doi: 10.1089/hum.2024.096. Epub 2024 Oct 25. PMID: 39450470
• Lentiviral Vector-Mediated Ex Vivo Hematopoietic Stem Cell Gene Therapy for Mucopolysaccharidosis IVA Murine Model
  Celik B, Rintz E, Sansanwal N, Khan S, Bigger B, Tomatsu S.
  Hum Gene Ther. 2024 Nov;35(21-22):917-937. doi: 10.1089/hum.2024.094. Epub 2024 Oct 24. PMID: 39446675
• Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy
  Rossi A, Romano R, Fecarotta S, Dell’Anno M, Pecorella V, Passeggio R, Zancan S, Parenti G, Santamaria F, Borgia F, Deodato F, Funghini S, Rupar CA, Prasad C, O’Callaghan M, Mitchell JJ, Valsecchi MG, la Marca G, Galimberti S, Auricchio A, Brunetti-Pierri N.
  Med. 2024 Nov 12:S2666-6340(24)00419-7. doi: 10.1016/j.medj.2024.10.021. Online ahead of print. PMID: 39547230
• Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)
  Sohn YB, Wang R, Ashworth J, Broqua P, Tallandier M, Abitbol JL, Jozwiak E, Pollard L, Wood TC, Aslam T, Harmatz PR.
  Mol Genet Metab Rep. 2023 Dec 28;38:101041. doi: 10.1016/j.ymgmr.2023.101041. eCollection 2024 Mar. PMID: 38234862
• Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program
  Giugliani R, Gonzalez-Meneses A, Scarpa M, Burton B, Wang R, Martins E, Oussoren E, Hennermann JB, Chabrol B, Grant CL, Sun A, Durand C, Hetzer J, Malkus B, Marsden D, Merritt Ii JL.
  Orphanet J Rare Dis. 2024 May 7;19(1):189. doi: 10.1186/s13023-024-03176-z. PMID: 38715031
• Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease
  Kenney-Jung D, Korlimarla A, Spiridigliozzi GA, Wiggins W, Malinzak M, Nichting G, Jung SH, Sun A, Wang RY, Al Shamsi A, Phornphutkul C, Owens J, Provenzale JM, Kishnani PS.
  Mol Genet Metab. 2024 Feb;141(2):108119. doi: 10.1016/j.ymgme.2023.108119. Epub 2023 Dec 22. PMID: 38184429
• Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02)
  Byrne BJ, Schoser B, Kishnani PS, Bratkovic D, Clemens PR, Goker-Alpan O, Ming X, Roberts M, Vorgerd M, Sivakumar K, van der Ploeg AT, Goldman M, Wright J, Holdbrook F, Jain V, Benjamin ER, Johnson F, Das SS, Wasfi Y, Mozaffar T.
  J Neurol. 2024 Apr;271(4):1787-1801. doi: 10.1007/s00415-023-12096-0. Epub 2023 Dec 6. PMID: 38057636
• Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations
  Yoon JK, Schindler JW, Loperfido M, Baricordi C, DeAndrade MP, Jacobs ME, Treleaven C, Plasschaert RN, Yan A, Barese CN, Dogan Y, Chen VP, Fiorini C, Hull F, Barbarossa L, Unnisa Z, Ivanov D, Kutner RH, Guda S, Oborski C, Maiwald T, Michaud V, Rothe M, Schambach A, Pfeifer R, Mason C, Biasco L, van Til NP.
  Mol Ther. 2024 Nov 6;32(11):3847-3864. doi: 10.1016/j.ymthe.2024.09.024. Epub 2024 Sep 17. PMID: 39295144
• Effective Gene Therapy for Metachromatic Leukodystrophy Achieved with Minimal Lentiviral Genomic Integrations
  Tricoli L, Sase S, Hacker J, Pham V, Smith S, Chappell M, Breda L, Hurwitz S, Tanaka N, Castracani CC, Guerra A, Hou Z, Schlotawa L, Radhakrishnan K, Kurre P, Ahrens-Nicklas R, Adang L, Vanderver A, Rivella S.
  bioRxiv [Preprint]. 2024 Mar 14:2024.03.14.584404. doi: 10.1101/2024.03.14.584404. PMID: 38559013
• Long-term lineage commitment in haematopoietic stem cell gene therapy
  Calabria A, Spinozzi G, Cesana D, Buscaroli E, Benedicenti F, Pais G, Gazzo F, Scala S, Lidonnici MR, Scaramuzza S, Albertini A, Esposito S, Tucci F, Canarutto D, Omrani M, De Mattia F, Dionisio F, Giannelli S, Marktel S, Fumagalli F, Calbi V, Cenciarelli S, Ferrua F, Gentner B, Caravagna G, Ciceri F, Naldini L, Ferrari G, Aiuti A, Montini E.
  Nature. 2024 Dec;636(8041):162-171. doi: 10.1038/s41586-024-08250-x. Epub 2024 Oct 23. PMID: 39442556
• Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency
  Pham V, Tricoli L, Hong X, Wongkittichote P, Castruccio Castracani C, Guerra A, Schlotawa L, Adang LA, Kuhs A, Cassidy MM, Kane O, Tsai E, Presa M, Lutz C, Rivella SB, Ahrens-Nicklas RC.
  Mol Ther. 2024 Nov 6;32(11):3829-3846. doi: 10.1016/j.ymthe.2024.08.015. Epub 2024 Aug 22. PMID: 39169621
• Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy
  Bradbury AM, Bagel J, Swain G, Miyadera K, Pesayco JP, Assenmacher CA, Brisson B, Hendricks I, Wang XH, Herbst Z, Pyne N, Odonnell P, Shelton GD, Gelb M, Hackett N, Szabolcs P, Vite CH, Escolar M.
  Mol Ther. 2024 Jan 3;32(1):44-58. doi: 10.1016/j.ymthe.2023.11.014. Epub 2023 Nov 11. PMID: 37952085
• High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson’s disease
  Williams D, Glasstetter LM, Jong TT, Chen T, Kapoor A, Zhu S, Zhu Y, Calvo R, Gehrlein A, Wong K, Hogan AN, Vocadlo DJ, Jagasia R, Marugan JJ, Sidransky E, Henderson MJ, Chen Y.
  Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2406009121. doi: 10.1073/pnas.2406009121. Epub 2024 Oct 10. PMID: 39388267
• Long-Term Treatment of Gaucher Disease with Velaglucerase Alfa in ERT-Naïve Patients from the Gaucher Outcome Survey (GOS) Registry
  Deegan P, Lau H, Elstein D, Fernandez-Sasso D, Giraldo P, Hughes D, Zimran A, Istaiti M, Gadir N, Botha J, Revel-Vilk S.
  J Clin Med. 2024 May 9;13(10):2782. doi: 10.3390/jcm13102782. PMID: 38792324
• Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study
  Wallace EL, Goker-Alpan O, Wilcox WR, Holida M, Bernat J, Longo N, Linhart A, Hughes DA, Hopkin RJ, Tøndel C, Langeveld M, Giraldo P, Pisani A, Germain DP, Mehta A, Deegan PB, Molnar MJ, Ortiz D, Jovanovic A, Muriello M, Barshop BA, Kimonis V, Vujkovac B, Nowak A, Geberhiwot T, Kantola I, Knoll J, Waldek S, Nedd K, Karaa A, Brill-Almon E, Alon S, Chertkoff R, Rocco R, Sakov A, Warnock DG.
  J Med Genet. 2024 May 21;61(6):520-530. doi: 10.1136/jmg-2023-109445. PMID: 37940383
• 4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model
  Weaver FE, White E, Peek AM, Nurse CA, Austin RC, Igdoura SA.
  Hum Mol Genet. 2024 Nov 12:ddae153. doi: 10.1093/hmg/ddae153. Online ahead of print. PMID: 39530163