#163: A Hemoglobin Makeover: Curative and Transformative Therapies for SCD

December 24, 2025 | By Sam Masur

Audio

Join us in this episode with expert guest Dr. Mahvish Rahim (the Children’s Hospital at Montefiore) as we dive into the rapidly evolving world of curative and transformative therapies for sickle cell disease! From breaking down the science behind stem cell transplant and gene therapy to understanding how to choose the right candidates and counsel families, Dr. Rahim brings clarity to this exciting new era in SCD care.

Gene therapy and BMT for SCD: Pearls

1. There are two types of potentially curative/transformative treatments for children with sickle cell disease: bone marrow transplant (BMT) which is also referred to as stem cell transplant or gene therapy (GT).
2. Gene therapy and BMT both involve first going through chemotherapy to destroy the existing stem cells in the bone marrow, this is called conditioning chemotherapy. 
3. Key differences between BMT and GT for sickle cell disease:

• BMT requires donor stem cells from a HLA matched donor, a full sibling has a 25% chance of being a ‘perfect’ HLA match.
• GT is an option even if a donor isn’t available as it uses a patient’s own cells.
• BMT has been an option to cure SCD for decades.  GT is a new option.
• GT currently is only available to children who are  ≥12 years old.
• One risk of BMT is graft-versus-host-disease, GT does not carry this risk.
• Patients who have GT will still have higher than normal levels of hemoglobin S, patients who successfully undergo BMT will not.

BMT and Gene Therapy for SCD Notes 

Pathophysiology

• Sickle cell disease (SCD) arises from a single point mutation (substitution of valine for glutamic acid) on the gene HBB, which codes for hemoglobin beta chains. This results in the production of hemoglobin S, which polymerizes under stress (infection, dehydration, cold), deforming RBCs into sickled shapes.
• HLA (Human Leukocyte Antigen) genes encode proteins on the surface of cells that help the immune system distinguish “self” from “non-self”. Because 50% of the genes are inherited from each parent a child will always be a “half match” for a parent and have a 25% of being a “perfect match” with a full sibling.
• BMT (also call stem cell transplant) involves replacing the patient’s bone marrow cells (i.e. stem cells) with an HLA-matched donor’s stem cells.
• Gene therapy involves genetically modifying the patient’s own stem cells to increase healthy hemoglobin production.

Gene therapy for SCD

As gene therapy is a new treatment option without long-term data, Dr. Mahvish Rahim recommends referring to gene therapy as “transformative” rather than “curative” for sickle cell disease.

Gene therapy eligibility

• Age ≥12 years.
• Must meet burden-of-disease criteria (minimum number of vaso-occlusive crises and/or acute chest syndrome episodes).
• No donor required.

Gene therapy mechanism

There are currently two commercially available types of GT:

CRISPR-Cas9–based editing (↑ Hemoglobin F)

• CRISPR acts like “molecular scissors.”
• Disrupts regulatory elements to increase fetal hemoglobin (HbF).
• Tip: Dr Mahvish Rahim suggests an easy way to remember the mechanism is thinking of hydroxyurea, a medication which also increases HbF

Lentiviral vector insertion (↑ Hemoglobin A)

• Adds a functional β-globin–like gene.
• Results in ~50% Hemoglobin A 
• Remaining hemoglobin is a mix of HbS and endogenous HbA/F.
• Tip: Dr Mahvish Rahim recommends thinking of the mechanism as analogous to a simple blood transfusion, which also increases the amount of HbA

Gene therapy process

• The patient’s own stem cells are collected and genetically modified.
• The patient is admitted to hospital for typically ~6-8 weeks.
• The patient undergoes myeloablative conditioning chemotherapy, similar to BMT. This causes destruction of the patient’s stem cells within their bone marrow.
• Modified stem cells reinfused. This process looks similar to when a patient receives a simple blood transfusion.
• Engraftment, which is the term for when the infused stem cells establish themselves in the bone marrow, takes ~45 days.

Risks of GT

• Most risks stem from conditioning chemotherapy.
• Short term affects from chemotherapy that all patient will have (which will resolve): nausea, vomiting, mucositis, diarrhea, alopecia.
• A key short term risk of chemotherapy is severe infection.
• Long term: infertility from conditioning chemotherapy.
• Uncertain long-term outcomes, particularly related to vasculopathy.
• Unlike BMT, there is no risk of GVHD.
• Note that chronic end organ damage already caused by SCD will not be reversed with GT.

BMT for SCD

Bone marrow transplant (BMT) and stem cell transplant (SCT) are interchangeable terms. The type is transplant used as a curative therapy for SCD is allogeneic meaning the stem cells are from a donor.

Who are candidates for BMT?

• Children with significant disease burden from SCD and who have a HLA matched sibling donor are classically considered good candidates
• Related donors are preferred over unrelated due to matching at minor antigens
• New studies have been exploring transplant with haploidentical donors – the term haploidentical means that 50% of HLA markers are the same
• Relative contraindications: lack of HLA matched donor, severe comorbidities that make transplant unsafe

BMT process

• An HLA matched donor’s stem cells are retrieved from their bone marrow
• The patient is admitted to hospital for typically ~6-8 weeks.
• Patient undergoes myeloablative conditioning chemotherapy. This causes destruction of the patient’s stem cells within their bone marrow.
• Donor stem cells reinfused. This is process looks similar to when a patient receives a simple blood transfusion.
• Engraftment, which is the term for when the infused stem cells establish themselves in the bone marrow, takes ~20-25 days.
• After a successful transplant the patient will ultimately have the same amount of HbS as their donor – a small amount if the donor has sickle cell trait or none if their donor does not

Risks of BMT

• Most risks stem from conditioning chemotherapy.
• Short term affects from chemotherapy that all patient will have (which will resolve): nausea, vomiting, mucositis, diarrhea, alopecia.
• Long term: infertility from conditioning chemotherapy.
• Immunosuppression required post-transplant but eventually weaned as immune reconstitution occurs.
• Graft-versus-host disease (GVHD): complication from donor immune cells attacking host. Early signs can include itchy rash classically beginning on palms/soles/ears and diarrhea

Fertility preservation 

• Myeloablative chemotherapy required for GT/BMT→ high likelihood of infertility.
• There may be financial barriers to accessing fertility preservation

Options for fertility preservation:

• Pubertal males: sperm banking
• Pubertal females: egg harvesting (time-dependent)
• Prepubertal males: testicular tissue cryopreservation (experimental)
• Prepubertal females: ovarian tissue cryopreservation (more established than testicular tissue cryopreservation)

Key take-home messages 

1. Early referral is helpful, discussion does not obligate families to pursue transplant or gene therapy but provides time to begin understanding options
2. BMT with a fully HLA matched sibling donor is the most established curative approach for children with SCD, but gene therapy has just recently become commercially available and provides an option for those without matched sibling donors
3. Both gene therapy and BMT involve chemotherapy, and the process includes a long hospitalization. Many of the key risks for both are related to chemotherapy. 
4. Equity and access to curative options remain major challenges—advocacy and awareness are critical.

Links

Dr. Mahvish Rahim suggests joining the registry to be a potential stem cell donor: Be The Match! 

Goal

Listeners will explain the pathophysiology of sickle cell disease and the principles of BMT and gene therapy to support informed discussions and timely referral for potentially curative treatment options.

Learning Objectives

After listening to this episode listeners will…  

1. Describe the basic pathophysiology of SCD and basic mechanic of curative or transformative therapies 
2. Differentiate between BMT and gene therapy, including donor requirements, processes, risks, and expected outcomes.
3. Recognize the short- and long-term risks of conditioning chemotherapy, including infertility and immune suppression, and understand expected post-therapy monitoring.
4. Discuss ethical and access considerations surrounding curative therapy for SCD, especially in historically marginalized populations.

Disclosures

Dr Rahim reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

Chisholm JC, Rahim M, Chiu C, Masur S. “#163 A Hemoglobin Makeover: Curative and Transformative Therapies for SCD”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ December 24, 2025.