A recently developed gene therapy reversed disease symptoms in two sickle cell anemia (SCA) patients, opening the door for a potentially new approach for this patient population, especially those in resource-challenged areas.
“One year after treatment of our first patient and 6 months after treatment of our second patient, both have seen a remarkable improvement in the quality of life due to remarkable reduction in disease symptoms. This includes near elimination of chronic pain and sickling events and improved anemia,” said study author Punam Malik, MD, Director of Cincinnati Children's Comprehensive Sickle Cell Center. “Although it's still early post-treatment, these preliminary results are quite promising. If sustained this therapy will provide a transportable, safe, and feasible gene therapy for all SCA patients.”
While sickle cell disease (SCD) is rare in the U.S., there is a huge global burden, noted Malik. “There are 2,000 children with sickle cell disease born per year in the U.S. while 300,000 babies are born with the disease every year in Africa alone,” she emphasized. “And so, we need more curative therapies because there just aren't enough.
“These children cannot afford hydroxyurea, the approved drug for SCD, or the necessary monitoring for the treatment,” she explained, adding that they also do not have the option of a myeloablative transplant from a matched sibling. Even if this approach was available, only 15 percent have a match, leaving 85 percent of patients without a curative option, Malik noted.
Recognizing this unmet need, Malik and her team sought to develop a new treatment approach to fill the void for these patients. “Based upon our preclinical data, we embarked upon a Reduced Intensity Conditioning (RIC) Phase I/II Pilot Study on Gene Transfer in Patients with SCA with a modified γ-Globin LV (NCT02186418), hypothesizing this approach will be safe, feasible, and efficacious,” according to study authors.
“Moreover, RIC will have significantly less toxicity [and] costs, and be implementable in many transplant centers, including those in some of the resource-poor countries, where supportive therapies for myeloablative transplants are unavailable, and where majority of SCA patients exist.”
Malik and her colleagues developed the gene therapy utilizing a modified gamma globin lentivirus vector to transfer a healthy fetal hemoglobin gene into a patient's hematopoietic stem cells (HSC).
While the fetal hemoglobin gene normally switches off shortly after birth, researchers have observed some adults never stop producing fetal hemoglobin; when sufficient quantities are present, red blood cell sickling is prevented. “The lentivirus vector we developed carries the fetal hemoglobin gene,” Malik explained. “This gene therapy approach places a fetal hemoglobin gene in the bone marrow cells that cannot switch off.”
Researchers collected CD34+ HSC via bone marrow harvest and/or plerixafor mobilized peripheral blood stem collection, selected for CD34+ cells and transduced, according to Malik.
“Following delivery of the vector into the patient's stem cells, the patient receives reduced intensity chemotherapy before the infusion of the genetically corrected cells,” she explained. A single dose of IV melphalan was administered 36 hours prior to infusion of γ-globin modified-HSC.
Following infusion, the investigators monitored patients for adverse events, engraftment, vector copy number, modified fetal hemoglobin expression, and clinical features of SCA.
To date, researchers have treated two patients with this new approach and initial findings are promising.
The patients (35 and 25 years old) both had severe disease. Patient 1 received 1x106 CD34+ cells/kgbw compared to 6.9x106 CD34+ cells/kgbw for patient 2. “Patients recovered their blood counts within a week to 10 days and recovered from the chemotherapy effects by 2 weeks,” Malik noted.
Since receiving this treatment, both patients have seen improvements in their disease symptoms. “Twenty percent of the circulating hemoglobin in patient 1 is coming from the vector, and this has resulted in a tremendous improvement in their sickle cell disease symptoms,” Malik reported. “The second patient is not producing as much as the first patient, at last analysis it was about 12 percent fetal hemoglobin, but that is sufficient to be completely be free of symptoms of sickle cell disease.”
In the 2 years prior to transplant, both patients were admitted more than 5-6 times per year for pain crises, according to the researchers. Additionally, they required opiates to manage chronic pain. One year following therapy, the first patient no longer requires daily oral opioids and has had one acute sickle cell event. Patient 2 no longer uses oral opioids and has had no vaso-occlusive events, investigators reported.
Building on the initial success of the therapy, Malik and her team plan to continue to explore the potential of this approach.
“In this phase I/II trial, we are approved for 10 patients, so our goal this year is to recruit more,” Malik noted. And while the team is in the rapidly recruiting phase right now, they are already looking at how they can expand the impact of this therapy.
“The first two patients were patients that we learned a lot from and I think it will only get better,” Malik told Oncology Times. “From the lessons learned we will only continue to improve our methodology.
“And it is our hope to lower the age to children because this gene therapy has implications for all sickle cell disease patients.”
If further study solidifies the benefit of this approach, it has a variety of practice implications.
“This therapy has the potential to be a curative option available to children as soon as they are diagnosed with sickle cell disease,” noted Malik. “We could treat these patients before they ever develop symptoms of the disease.”
Many adults with sickle cell disease have chronic organ damage, making it difficult for them to withstand myeloablative transplant. “Our approach with reduced intensity transplant offers similar benefit with less toxicity,” Malik explained.
And while there are other curative gene therapy options being developed in the field, she noted the value of having multiple choices. “Patients can choose whether they want a mild intensity regimen with fewer side effects that provides symptom relief, or they want to go for complete replacement of their sickle bone marrow with normal bone marrow from a sibling or genetically corrected cells.”
When asked what she hopes for the future of this gene therapy, Malik said, “We want this therapy to translate into a one-time cure that is available to all patients. And it can be, because everyone matches their own cells, so everyone is their own donor.”
Given the global burden of sickle cell disease, this gene therapy has the potential to transform the treatment of the disease and patient outcomes worldwide.
With the available therapeutic approaches, it is difficult for resource-challenged parts of the world to provide effective treatment. For instance, myeloablative preconditioning is normally used in bone marrow transplants, which is associated with a number of side effects, including severe infections that often require extensive inpatient care.
Therefore, this is not a treatment that can be performed outside of large medical centers with the means to provide the necessary care. In turn, patients in underdeveloped areas, where the disease is most common, including Africa, India, and South America, have limited access to this treatment regimen.
This is why the reduced-intensity preconditioning that is the cornerstone of this new approach is potentially revolutionary for increased access to effective treatments. Given it is less toxic with a lower cost, more patients could benefit from this therapy at a global level.
“We are working to create a curative therapy that can be widely applicable,” Malik noted. “If there is sustained benefit, this gene therapy could provide a transportable and effective treatment approach for SCA in regions that do not currently have access to the same level of care as more developed areas.
“Our goal is for this gene therapy to become a curative option that can be utilized in small transplant centers not only in the U.S. but worldwide,” she concluded.
Catlin Nalley is associate editor.