ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

December 26, 2019
3 min read

New gene therapy appears safe, feasible for sickle cell disease

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David A. Williams

ORLANDO — Significant induction of fetal hemoglobin after the infusion of CD34-positive cells occurred among a small cohort of patients with sickle cell disease, according to data from a phase 1 gene therapy feasibility study presented at ASH Annual Meeting and Exposition.

Researchers observed improvements in fetal hemoglobin and other hematologic measures among five patients, whereas none experienced adverse events associated with sickle cell disease, including vaso-occlusive pain and respiratory or neurological events.

“It has been known for some time that the severity of sickle cell disease is attenuated in patients who have a high level of persistent fetal hemoglobin expression, David A. Williams, MD, professor of pediatrics at Harvard Medical School and chief of hematology/oncology at Boston Children’s Hospital, said during a press conference. “In utero, one expresses almost all of their hemoglobin as fetal hemoglobin. After birth, the expression of fetal hemoglobin shuts off and adult hemoglobin turns on. In patients with sickle cell disease, that’s when the sickle cell mutation appears.”

This process is relevant to clinicians because when they see children in the first 6 months to 1 year of life, there are no symptoms of sickle cell disease, and after the switch occurs, patients develop disease-related complications, according to Williams, a co-author of the study.

“Recent basic science studies have led us to understand, at a molecular level, the regulation of that hemoglobin switch and the transcription factor called BCL11A that is a major component of that hemoglobin switch,” Williams said. “Our approach was to take this basic science finding and develop an antiviral gene therapy vector that leads to the knockdown of the repressor BCL11A. This induces the gamma globin back on the fetal hemoglobin but also simultaneously silences the mutated sickle globin. The advantage of this approach is that the sickling hemoglobin is downregulated at the same time that fetal hemoglobin is induced.”

The new lentiviral vector, called shmiR, targets BCL11A.

“The advantage of this is that it delivers a more physiologic payload that resembles a more endogenous microRNA,” Williams said. “It also allows us to express this only in developing red cells, which avoids any toxicity in the stem cell compartment or in B cells.”

The investigators mobilized patients’ peripheral stem cells using the bone marrow stimulant plerixafor (Mozobil, Sanofi-Aventis), isolated CD34-positive cells and sent them to a cell-processing facility for transduction with the shmiR lentivirus vector and cryopreservation.

Patients were given a preconditioning regimen of busulfan for 4 days, 2 to 5 days before infusion of the transduced CD34-positive cells.


The first six patients in the adult cohort received cell doses that ranged from 3.3 x 106/kg to 8.3 x 106/kg. Vector copy number, a measure of gene transfer efficacy, ranged from 2.8 to 6.9, and proportion of cells transduced ranged from 93.1% to 100%.

Williams presented preliminary data on the first three adults with more than 6 months of follow-up and two adolescents treated more recently.

Results showed significant induction of fetal hemoglobin after the infusion of CD34-positive cells, ranging from 42.8% in one patient 5 months after infusion to 23.8% in another patient 18 months after infusion. Researchers also observed an overall increase in the number of F cells and a stable yet high fetal hemoglobin-to-F-cell ratio in each patient.

No patients who received gene-edited CD34-positive cells reported vaso-occlusive pain, a hallmark of sickle cell disease, during follow-up. There were no respiratory or neurological events reported, as well as no unplanned blood transfusions for any of the study patients. One patient experienced recurrent priapism after gene therapy.

“We have shown that BCL11A is a very effective target in sickle cell disease and that our shmiR vector is safe, with very efficient transduction of stem cells and no adverse events related to the vector,” Williams said. “The shmiR works very well, with broadly expressed hemoglobin and significant attenuation of sickle cell disease-related symptoms.”

Williams and his group have received institutional review board approval to move forward with a multicenter phase 2/phase 3 study, and the investigators are already planning expansion of the pilot trial to include 15 patients and to evaluate additional biomarkers. – by Drew Amorosi


Esrick BE, et al. Abstract LBA-5. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.

Disclosures: Williams reports being a co-founder of Alerion Biosciences and Orchard Therapeutics; advisory/board of directors roles with Novartis and Orchard Therapeutics; patents, royalties and research funding from bluebird bio and Orchard Therapeutics; and payments from bluebird bio through a Boston Children’s Hospital institutional licensing agreement, with the potential for future royalty/milestone income. Please see the abstract for all other authors’ relevant financial disclosures.