Sickle Cell Disease: Centers of Excellence And Gene Therapy
July 11, 2020
Sickle cell disease (SCD) is a hemoglobinopathy associated with defective ‘sickle’ red blood cells. Two hemoglobinopathies, β-thalassemia and SCD, are different in the following way. β-Thalassemia has low or absent production of β-globin, while SCD has defective β-globin due to a specific mutation leading to defective hemoglobin.

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Introduction To Sickle Cell Disease
Genetically, SCD is inherited in the autosomal recessive manner with only one gene being affected: the gene of the β-hemoglobin subunit that typically has the GAG to GTG mutation, resulting in the Glu-to-Val substitution in position 6. Despite the single-gene, single-mutation nature, SCD is a multiorgan, clinically heterogeneous disease. A plethora of medical literature describes signs and symptoms of the disease, but for me as a non-clinician, what stands out the most is the horror of debilitating pain and perpetual fatigue. For many patients, the quality of life is poor. Sickle Cell Anemia (SCA) is the most severe form of SCD, and is the focus of many clinical trials of disease-modifying treatments.

Currently, the approved treatment with a curative potential is an HLA-matched transplant. However, as you can guess, for multiple socioeconomic reasons, finding a donor is not easy, with less than 1/4 of all patients having this option. Unfortunately, other approved treatments do not have curative or disease-modifying potential.
Pipeline Of Cell And Gene Therapies For Sickle Cell Disease
Trying to achieve a long-lasting and, hopefully, curative effect, many companies and academic groups are designing novel cell and gene therapy (CGTx) approaches to treat SCD. A haploidentical transplant is in Phase 3 clinical development, while gene therapies are in Discovery through Phase 3/Registration, as shown in the pipeline below (expands to full screen).

General Therapeutic Strategies
Let’s look at a few general strategies before discussing specific GTx modalities.

0 – To deliver a healthy β-globin gene

Purposefully, I call it ‘Strategy Zero’ because, unlike for some other autosomal recessive, single-gene diseases, this strategy is not a slam dunk for SCD. Notably, the β-globin gene is large, and gene silencing is a problem. Scientists have been trying to design a vector that can fit the gene and all regulatory elements to achieve safety and efficiency of gene expression. Currently, there is no such therapy in the pipeline, yet.

1 – To have fetal hemoglobin do the job for adult hemoglobin

First, there are two hemoglobins, fetal (HbF) and adult (HbA). HbF is present before birth, and its level declines steadily after birth. In contrast, the production of HbA ramps up after birth, and HbA becomes the main hemoglobin carrying oxygen in healthy adults. Consequently, HbA is the most common.

The relevance of HbF to SCD management is the following: if you increase the amount of HbF, you could compensate for defective HbA. This is one of the approaches used in GTx development. Scientists noticed that elevated HbF levels compensate for HbA deficiency in β-thalassemia and have a potent anti-sickling effect in SCD, reducing symptom severity.

How can HbF be increased?

While HbA has 2 α and 2 β chains, HbF has 2 α and 2 γ chains. Therefore, one drug development approach is to increase γ-globin production.

Conveniently, BCL11A plays a major role in repressing γ-globin gene expression. Therefore, BCL11A suppression (by creating specific mutations) results in persistence of HbF.

2 – To reduce sickling properties of defective HbA

Instead of tackling the disease-causing Glu-to-Val mutation in position 6, scientists noticed that the Glu-to-Thr change in position 87 of β-globin provides compensatory anti-sickling properties.
Sickle Cell Gene Therapy Examples
For the purpose of the article, we classify gene therapy candidates into 1) lentivirus-mediated gene transfer and 2) gene editing.

Lentiviral vector-mediated gene transfer

First, the most advanced therapy is Lentiglobin bb305 (HPV569 vector), by Bluebird Bio (formerly Genetix Pharma), currently in Phase 3/Registration. It has the Glu to Thr change in position 87. After the original LG001 trial, the vector was optimized, and new Ph1/2 trials HGB-205 and HGB-206 were conducted in France and the U.S., respectively.

Second, LentiV shRNA targeting BCL11A uses erythroid-specific shRNA that induces HbF in human erythroid cells derived from hematopoietic stem cells (HSCs).

Other lentiviral vectors include GLOBE (San Raffaele, Italy), RVT-1801 (Aruvant, Cincinnati Children’s), TNS9.3.55 (Memorial Sloan Kettering, halted development), and AS3-FB (UCLA).

Gene Editing

As compared to gene transfer/addition, gene editing has an advantage of not losing efficacy due to gene silencing (at least as currently believed). Examples of gene editing approaches to treat SCD include CRISPR/Cas9, zinc figure nucleases (ZFN), nuclease-free editing, and base editing. Most of editing happens ex vivo in patient’s HSCs. However, in vivo approaches are on the rise too. Editing tools are delivered using primarily viral vectors (lentiviral or AAV) or electroporation. The pipeline figure above provides details on some of these approaches (expand to full screen).
Clinical Trial Centers
Importantly, sickle cell disease is a rare condition, with ~100,000 people living with the disease in the U.S. Therefore, not many hematologists consider themselves experts in the disease, and not many centers have the experts. Then, where are SCD experts located? Where do patients go if they want to enroll into a trial? And what if patients are looking specifically for a gene therapy trial?

Below is the map showing clinical sites that have been conducting interventional trials in SCD:

  • Sites activated in the past 12 months (green),
  • Sites with CGTx experience (orange),
  • All other sites with interventional trials (blue).

Total # of trails = 45. Total # of sites = 151. Source:

To obtain this refined dataset, we applied the following Exclusion criteria:

  • Conditions: trials where SCD is one of many diseases
  • Trial Phase: no phase information
  • Sponsor: no industry sponsor involvement
  • Trial type: observational or expanded access trials
  • Dates: trials completed before 2016, or trials not updated in the past ~5 years
  • Sites: exUS sites, trials without appropriate clinical site information
Of 151 site, 30 sites have initiated at least one interventional clinical trial in sickle cell disease in the last 12 months (on map: green) and 29 sickle cell centers have had at least one trial involving a novel cell/ gene therapy (on map: orange). See tables below with the names of the institutions that represent these 30 & 29 sites (expand for full screen).
Does the sickle cell disease gene therapy development get sufficient attention from the scientific and drug development community?
For example, at the 23rd Annual Meeting of ASGCT, 22 posters and oral presentations highlighted progress towards novel and potentially curative treatments for SCD. Comparing to other disorders, SCD is one of the most discussed, both in 2019 and 2020. (For more detail, see our insights article on non-oncology diseases at ASGCT).

Notably, the 2020 conference featured a broad spectrum of SCD gene therapy studies, including in vitro, in mice and non-human primates, patient samples, as well as clinical trials. Unsurprisingly, ex vivo approaches are dominant. However, in vivo approaches are being gradually developed, with most notable examples being HDAd5/35++ vectors by University of Washington, Seattle (posters 199, 373, 629, 810, 811 and talks 546 and 1322) and AAVHSC-delivered nuclease-free editing by Homology Medicines.

In conclusion, SCD seems to get significant attention from the CGTx development community as compared to many other rare diseases. However, not many centers have an option to enroll patients in such trials. Optimistically, a multitude of preclinical programs gives hope for more trials to open up in the future.

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Disclaimer: This article is for the educational purpose only. It is the property of BioHeights LLC. This article is written based only on non-confidential information provided on company websites, in press releases and scientific publications, and on BioHeights LLC and its members are not responsible for any damages resulting from reading this blog article. BioHeights LLC takes no responsibility for completeness or correctness of this article and its contents.
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