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

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

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.

Study Overview

• Status: Recruiting
• Conditions: CD40L-HyperIgM Syndrome
• Intervention / Treatment: Drug: Busulfan; Drug: Palifermin; Drug: Sirolimus; Drug: Alemtuzumab; Biological: Base-edited hematopoietic stem and progenitor cells; Biological: Base-edited T lymphocyte cells

Detailed Description

Study Description:

This is a single participant gene therapy study to provide a participant with CD40L c.658C>T; p.Q220X-Hyper IgM syndrome with autologous base-edited hematopoietic stem/progenitor cells (HSPC) and base-edited T cells (BE T). The study hypothesis is that base edited HSPCs will be repaired efficiently and safely to restore CD40L expression and improve immune function long term. BE T cells will provide functional T cells to support subject against immunodeficiency and lymphopenia.

The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan administered once daily for 2 days with a daily target AUC of 4500 micromol*min/L or a cumulative AUC of 9000 micromol*min/L (approximately 6 mg/kg) and serotherapy (alemtuzumab (Campath)) 10 mg/m^2 total dose divided over 3 days by subcutaneous injection on days -21, -20, and -19. Following infusion, the participant will be evaluated at months 3, 6, 9, 12, 18, 24. Long-term annual follow up will be performed on a separate protocol.

Base edited autologous T cells will be administered at 2 weeks following BE HSPC infusion that function as 'donor lymphocyte infusions' to protect the patient from the diseaserelated T-cell immunodeficiency and alemtuzumab-related lymphopenia. Subsequent doses of BE T cells may be infused monthly as indicated to achieve T cell reconstitution for treatment of infections.

Objectives:

• Primary Objective: To determine the safety and efficacy of BE HSPC CD40L and BE T cells.
• Secondary Objectives: To determine restoration of CD40L expression and immune function

• Exploratory Objectives:

  • Assess for potential unintended edits
  • Kinetics of immune reconstitution

Endpoints:

• Primary Endpoint:

  • Efficacy determined by percentages of corrected alleles
  • Safety determined by toxicities related to infusion of Study Cell Product

• Secondary Endpoints:

  • Level of CD40L expression in peripheral blood T cells
  • IgG production
  • Response to immunization

• Exploratory Endpoints:

  • Repeat WES at 24 months after study cell product infusion
  • Evaluate for gene correction levels in peripheral blood CD34s and isolated immune cell lineages

• Study Type: Interventional
• Enrollment (Estimated): 1
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Suk S De Ravin, M.D.; Phone Number: (301) 496-6772; Email: sderavin@niaid.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 (800) 411-1222; Email: ccopr@nih.gov
      • Contact: Suk De Ravin, MD, PhD; Phone Number: 301-496-6772; Email: sderavin@niaid.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

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

EXCLUSION CRITERIA:

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Drug: Busulfan; 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; Drug: Palifermin; 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).; Drug: Sirolimus; Immunophilin drug, will start on day -1, targeting a trough level between 4-12 ng/mL.; Drug: Alemtuzumab; Serotherapy agent, 10 mg/m^2 on days -21, -20 and -19; Biological: Base-edited hematopoietic stem and progenitor cells; The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning.; Biological: Base-edited T lymphocyte cells; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of CD40L expression in peripheral blood T cells	To determine restoration of CD40L expression and immune function	Through end of study
IgG production	To determine restoration of CD40L expression and immune function	Through end of study
Response to immunization	To determine restoration of CD40L expression and immune function	Through end of study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Suk S De Ravin, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2025
• Primary Completion (Estimated): October 28, 2027
• Study Completion (Estimated): October 28, 2027

Study Registration Dates

• First Submitted: May 6, 2025
• First Submitted That Met QC Criteria: May 6, 2025
• First Posted (Actual): May 7, 2025

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 23, 2026

More Information

Terms related to this study

• Keywords: Gene Editing; base editing
• Additional Relevant MeSH Terms: Primary Immunodeficiency Diseases; Pathologic Processes; Genetic Diseases, Inborn; Immune System Diseases; Disease; Hematologic Diseases; Immunologic Deficiency Syndromes; Blood Protein Disorders; Genetic Diseases, X-Linked; Dysgammaglobulinemia; Syndrome; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome, Type 1; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Hydrocarbons, Acyclic; Hydrocarbons; Biological Factors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Macrolides; Lactones; Intercellular Signaling Peptides and Proteins; Fibroblast Growth Factors; Alemtuzumab; Sirolimus; Busulfan; Fibroblast Growth Factor 7
• Other Study ID Numbers: 10002385; 002385-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No