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A Brief primer on gene therapy and discussion of transition in sickle cell disease

Suzie Noronha, MD and Sharee Turpin, MA

Pediatric Sickle Cell Program

Pediatric Hematology/Oncology

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Objectives

1. To briefly review the genetics and pathophysiology of sickle cell disease as a foundation for the need for better treatments
2. To discuss disease modifying treatments and curative therapy
3. To discuss the benefits and challenges associated with gene therapy
4. To be aware of ongoing challenges of transition for the many patients who are not candidates for gene therapy

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Genetics

Single point mutation
SS>SC>Sb⁺thal>Sb⁰thal
Severity:

SS=Sb⁰thal>SC>Sb⁺thal

Other sickle variants

Sickle Hb O-Arab
Sickle Hb E
Sickle HPFH
Sickle Hb D

University of California Museum of Paleontology's Understanding Evolution (http://evolution.berkeley.edu)

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Steinberg MH in Goldman’s Cecil Medicine 23^rd ed. 2007

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Complications

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Piel et al. 2017

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Available therapies

Transfusions

Abnormal TCD
Secondary stroke prevention
Acute chest syndrome
Iron overload & alloimmunization

Hydroxyurea

BABYHUG: can start at 9mo
Effective in reducing VOC, ACS
Evolving landscape
Compliance, misconceptions

Bone marrow transplantation

Curative
Limited by donor availability
Best outcomes with matched sib
Currently considered for severe disease or avoidance of severe disease

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Gene therapy

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FDA approved gene therapy products (2023)

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Lentiviral vector used to insert functioning beta-globin gene

Cas9 editing of BCL11A enhancer to knock down BCL11A

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Results – Lentiglobin (Lyfgenia)

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https://www.lyfgenia.com/clinical-trial-results

Significant reduction in VOE/ACS
No stroke in 2 patients with hx stroke
Hemolysis reduced (not eliminated)
2 cases of AML/MDS assessed to not be associated

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Results – Exa-cel (Casgevy)

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97% free from VOE x 12 months
No cancers
Hemolytic markers normalized
Side effects related to busulfan conditioning

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Sharma A, How I treat sickle cell disease with gene therapy, Blood, 2024

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Challenges and remaining questions

Eligibility

Non severe genotypes/phenotypes?

Cost

$2-3 million vs $100,000
Fertility preservation – who is paying?

Process

Collection has been onerous

Clinical questions

Utility for patients with hx of stroke/vasculopathy
Impact on other complications (pulmonary hypertension, nephropathy, etc)
Ongoing hemolysis - curative or transformative?
Secondary cancer risk?

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For most people living with sickle cell disease…

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Advances in SCD care

Universal newborn screening
Penicillin prophylaxis
Pneumococcal vaccination
Secondary prophylaxis of stroke
Primary prevention of stroke with transcranial Doppler
Hydroxyurea
Matched-sibling bone marrow transplantation

Smith et al 2006

Wailoo NEJM 2017

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Age‐related sickle cell complications

Blinder 2013

Healthcare administrative claims from the Florida (1998–2009), New Jersey (1996–2009), Missouri (1997–2010), Kansas (2001–2009), and Iowa (1998–2010) Medicaid programs. A total of 3,208 patients (Florida: 1,550, New Jersey: 992, Missouri: 489, Kansas: 121, Iowa: 56)

�SCD complications by age. Pulmonary complications include: chronic obstructive pulmonary disease, pneumonia, asthma, pulmonary hypertension, and acute chest syndrome; cardiovascular complications include: congestive heart failure, cardiomegaly, arrhythmia, and cardiomyopathy; other complications include: leg ulcers and avascular necrosis.�

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Mortality spike in transition period

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Karkoska and McGann 2024

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Personal perspectives on the transition process and on how GC can support transition

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Conclusions

Sickle cell disease is a highly morbid condition causing shortened lifespan
Relatively few therapies with multiple barriers
Gene therapy effective at substantially reducing pain episodes
But challenges and unanswered questions for gene therapy remain
For most patients with sickle cell disease, the transition period remains a precarious time
Interdisciplinary support for transitioning AYA will help

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References

Frangoul H et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. NEJM 2024; 390:1649-1662.
Kanter J et al. Lovo‐cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB‐206 study. Am J Hematol. 2023;98:11–22.
Karkoska KA, McGann PT. Trends in Sickle Cell Disease Mortality: 1979–2020. Pediatrics. 2024;154(6):e2024067341
Piel FB, MH Steinberg, DC Rees. Sickle cell disease. N Engl J Med 2017;376:1561-1573.
Sharma A. How I treat sickle cell disease with gene therapy. Blood 2024;144:2693-2705.
Wailoo K. Sickle Cell Disease - A History of Progress and Peril. N Engl J Med 2017; 376:805-807.

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