Base Editing Hematopoietic Stem Cell and T Cell Gene Therapy for CD40L-HyperIgM Syndrome: Single Patient Study

Summary

Background: X-linked hyper-IgM (HIGM) syndrome is caused by a mutation in the CD40 ligand (CD40L) gene. People with this disease have white blood cells that do not work properly. These people are at risk of severe infections and autoimmune diseases. Researchers want to know if these base-edited stem cells and T cells can help people with CD40L-HIGM syndrome. Objective: To test base-edited stem cells and base-edited T cells in 1 person with CD40L-HIGM syndrome. Eligibility: A single male with CD40L-HIGM syndrome. Design: A single participant is planned to receive a single dose of edited stem cells and supportive treatment with edited T cells. Participant stem and T cells will undergo base editing to repair the mutation. In preparation for the gene therapy, the participant will receive busulfan chemotherapy and alemtuzumab. After treatment, the participant will have follow-up visits every few months in the first 2 years after treatment. Long-term visits will continue annually for 15 years.

Timeline

Start

2025-07-16

Primary completion

2027-10-28

Completion

2027-10-28

Publications

• Background Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003 Nov;82(6):373-84. doi: 10.1097/01.md.0000100046.06009.b0.
• Background Kracker S, Gardes P, Durandy A. Inherited defects of immunoglobulin class switch recombination. Adv Exp Med Biol. 2010;685:166-74. doi: 10.1007/978-1-4419-6448-9_15.
• Background Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C, Ochs HD, Rawlings DJ, Scharenberg AM, Torgerson TR. Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome. Blood. 2016 May 26;127(21):2513-22. doi: 10.1182/blood-2015-11-683235. Epub 2016 Feb 22.
• Background Ferrari S, Vavassori V, Canarutto D, Jacob A, Castiello MC, Javed AO, Genovese P. Gene Editing of Hematopoietic Stem Cells: Hopes and Hurdles Toward Clinical Translation. Front Genome Ed. 2021 Mar 31;3:618378. doi: 10.3389/fgeed.2021.618378. eCollection 2021.
• Background Lazzarotto CR, Katta V, Li Y, Urbina E, Lee G, Tsai SQ. CHANGE-seq-BE enables simultaneously sensitive and unbiased in vitro profiling of base editor genome-wide activity. bioRxiv [Preprint]. 2024 Mar 30:2024.03.28.586621. doi: 10.1101/2024.03.28.586621.
• Background de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla FA, Kanariou M, Damrongwatanasuk R, Kuo CY, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter D, DiGiovanni D, Dhalla F, Farmaki E, Speckmann C, Espanol T, Shcherbina A, Hanson IC, Litzman J, Routes JM, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JD, Chou J, Abbott JK, van Montfrans J, Gonzalez-Granado LI, Bunin N, Kutukculer N, Gray P, Seminario G, Pasic S, Aquino V, Wysocki C, Abolhassani H, Dorsey M, Cunningham-Rundles C, Knutsen AP, Sleasman J, Costa Carvalho BT, Condino-Neto A, Grunebaum E, Chapel H, Ochs HD, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo LD, Roifman CM. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292. doi: 10.1016/j.jaci.2016.07.039. Epub 2016 Sep 30.
• Background Gennery AR, Khawaja K, Veys P, Bredius RG, Notarangelo LD, Mazzolari E, Fischer A, Landais P, Cavazzana-Calvo M, Friedrich W, Fasth A, Wulffraat NM, Matthes-Martin S, Bensoussan D, Bordigoni P, Lange A, Pagliuca A, Andolina M, Cant AJ, Davies EG. Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002. Blood. 2004 Feb 1;103(3):1152-7. doi: 10.1182/blood-2003-06-2014. Epub 2003 Oct 2.
• Background Vavassori V, Mercuri E, Marcovecchio GE, Castiello MC, Schiroli G, Albano L, Margulies C, Buquicchio F, Fontana E, Beretta S, Merelli I, Cappelleri A, Rancoita PM, Lougaris V, Plebani A, Kanariou M, Lankester A, Ferrua F, Scanziani E, Cotta-Ramusino C, Villa A, Naldini L, Genovese P. Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome. EMBO Mol Med. 2021 Mar 5;13(3):e13545. doi: 10.15252/emmm.202013545. Epub 2021 Jan 21.

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