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

NCT06959771 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10002385002385-I
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

CD40L-HyperIgM Syndrome

Keywords

base editing; Gene Editing

Outcome Measures

Primary Outcomes (2)

• Safety determined by toxicities related to the infusion of the Study Cell Products

  To determine the safety and efficacy of BE HSPC CD40L and BE T Cells

  Through end of study

• Efficacy determined by percentages of corrected alleles

  To determine the safety and efficacy of BE HSPC CD40L and BE T Cells

  Through end of study

Secondary Outcomes (3)

• Level of CD40L expression in peripheral blood T cells

  Through end of study

• IgG production

  Through end of study

• Response to immunization

  Through end of study

Study Arms (1)

Single Arm Study

EXPERIMENTAL

The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.

Biological: Base-edited hematopoietic stem and progenitor cells; Drug: Alemtuzumab; Drug: Sirolimus; Drug: Palifermin; Drug: Busulfan; Biological: Base-edited T lymphocyte cells

Interventions

Base-edited hematopoietic stem and progenitor cells BIOLOGICAL

The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning.

Single Arm Study

Alemtuzumab DRUG

Serotherapy agent, 10 mg/m\^2 on days -21, -20 and -19

Single Arm Study

Sirolimus DRUG

Immunophilin drug, will start on day -1, targeting a trough level between 4-12 ng/mL.

Single Arm Study

Palifermin DRUG

Mucositis prophylaxis agent, will be administered at 60 mcg/kg/day for 3 days before initiation of busulfan (days -6 to -4), as well as for the 3 days following study agent administration (days 1 to 3).

Single Arm Study

Busulfan DRUG

Myeloid conditioning agent, administered once daily (3 mg/kg) x 2 days, targeting a daily AUC of 4500 micromol\*min/L or a cumulative AUC of 9000 micromol\*min/L for the 2 days of therapy, if levels are available

Single Arm Study

Base-edited T lymphocyte cells BIOLOGICAL

The secondary study cell product is base edited autologous which will be administered as a one-time infusion two weeks following the infusion of the base-edited autologous HSPCs.

Single Arm Study

Eligibility Criteria

• Age: 37 Years - 120 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• This study is a single participant research study and to receive the study product, he needs to meet the following criteria:
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Has CD40L Q220X mutation
• Defective class switching
• Liver abnormalities (transaminases\>UL)
• Portal hypertension
• Consensus from Hepatology Consult to receive myeloid conditioning
• Ability to take oral medication and be willing to adhere to the intervention regimen
• Use of condoms or other methods to ensure effective contraception with partner
• Ability of subject to understand and the willingness to sign a written informed consent document

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Known allergic reactions to components of the BE HSPC study product or BE T cell product
• Febrile illness within two weeks of hospital admission for treatment
• Unwilling to submit their information as part of the alemtuzumab (Campath(R)) Distribution Program application or the Distribution Program committee has determined the participant is not qualified to receive alemtuzumab.
• NOTE: Alemtuzumab (campath) (IV formulation) is no longer distributed commercially. To receive product, the physician must contact the program for the participant. If the participant is not willing to consent to submit their info (demographics, contact information, and rationale for use) to the program such that we can obtain the drug, then we cannot proceed with conditioning; therefore no transplant will occur on this protocol. http://www.campath.com/
• Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than enrollment on observational studies and NIH protocols 94-I-0073 and 05-I-0213. Consideration for coenrollment in trials evaluating the use of a licensed medication will require the approval of the principal investigator in consultation with the medical monitor. Study staff should be notified of co-enrollment on any other protocol as it may require the approval of the principal investigator (in consultation with the medical monitor).

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (8)

• 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.

  PMID: 14663287 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.

  PMID: 20687504 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.

  PMID: 26903548 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.

  PMID: 34713250 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.

  PMID: 38585919 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.

  PMID: 27697500 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.

  PMID: 14525761 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.

  PMID: 33475257 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Alemtuzumab; Sirolimus; Fibroblast Growth Factor 7; Busulfan

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Organic Chemicals; Fibroblast Growth Factors; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Suk S De Ravin, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Suk S De Ravin, M.D.

CONTACT

(301) 496-6772; sderavin@niaid.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2025
• First Posted: May 7, 2025
• Study Start: July 16, 2025
• Primary Completion (Estimated): October 28, 2027
• Study Completion (Estimated): October 28, 2027
• Last Updated: March 27, 2026

Record last verified: 2026-03-23

Locations

US (1)