Sickle cell anemia: What’s new and what’s next

Sickle cell anemia is a challenging disease that causes significant morbidity and mortality across the lifespan. But new and emerging therapies, including two new gene therapy treatments available at Penn Medicine, offer hope to patients with this painful condition. 

To discuss the current treatment landscape, sickle cell experts Nadia Dawn Ali, MD, and Scott Alan Peslak, MD, PhD, recently joined the Penn Medicine Physician Interviews podcast. Dr. Ali is an Associate Professor of Medicine and Director of the Comprehensive Sickle Cell Program at Penn Medicine. Dr. Peslak is an Assistant Professor of Medicine and Gene Therapy Lead for the Comprehensive Sickle Cell Program and Comprehensive Adult Thalassemia Program.

Sickle cell anemia, also called sickle cell disease (SCD), is caused by a congenital mutation of the hemoglobin gene. SCD affects adult hemoglobin, which the body begins producing at around six months of age by creating misshapen hemoglobin molecules blood cells that block blood flow, causing painful vaso-occlusive episodes (VOEs) and complications such as stroke, infections, and organ damage.

Drug treatments for SCD

Just three disease-modifying medications have been approved for sickle cell disease:

• Hydroxyurea: This chemotherapy alters production of hemoglobin in the bone marrow, leading to the persistence of fetal hemoglobin, which is not affected by sickle cell mutations. “Hydroxyurea is really the number one tool that we have, and it has been well studied in children and adults,” Dr. Ali says. 
• L-glutamine: This amino acid helps decrease oxidative stress within red blood cells and can decrease the intensity and frequency of VOEs.
• Crizanlizumab: This IV infusion targets P-selectin to prevent blood cells from sticking inside the vessels. It can reduce the frequency of pain episodes.

Some patients are also treated with exchange transfusions, which involve removing the sickle cell blood and transfusing the patient with non-sickled blood. In patients with a history of stroke, this treatment can reduce the risk of recurrent stroke or other major complications.

Penn Medicine researchers pursue novel sickle cell treatments

Currently, hydroxyurea is the standard of care for SCD. At Penn Medicine, however, researchers are involved in ongoing efforts to develop new therapies for SCD. “Sometimes even with the maximal dose of hydroxyurea, we don’t achieve the effects we want, which are minimizing pain episodes, minimizing time in the hospital, and ensuring patients live productive lives,” Dr. Peslak says. 

In the search for new therapies, Dr. Peslak and his colleagues are targeting the fetal form of hemoglobin. They are pursuing treatments that may allow for the continued production of healthy fetal hemoglobin into adulthood. One line of research is studying a chemical that helps regulate cellular activity. Other projects are exploring medications used for other blood disorders, which may also have the potential to treat sickle cell disease. 

Meanwhile, researchers around the country are making progress in other ways, such as with therapies that alter red blood cells to make them healthier and reduce the amount of sickling. Penn Medicine is involved in large multisite clinical trials to test such emerging therapies. 

Gene therapy: a breakthrough for sickle cell disease

New gene therapy treatments are also transforming treatment for SCD. The FDA recently approved two gene therapy treatments. The use of these agents involves mobilization of stem cells from the bone marrow into the blood, where they are collected by apheresis. The cells are then genetically altered in a lab and manufactured in a process that takes three to four months. Patients then receive chemotherapy and an autologous stem cell transplant, which infuses the manufactured cells back into their bodies.

The two treatments work in slightly different ways: 

• Lovotibeglogene autotemcel (lovo-cel) is a gene addition therapy that contains genes with the instructions to make healthy, non-sickling hemoglobin.
• Exagamglogene autotemcel (exa-cel) is a gene editing approach that targets a protein, BCL11A, that represses the production of fetal hemoglobin. “By taking that brake off, we can increase the levels of (non-sickling) fetal hemoglobin,” Dr. Peslak says. 

While these treatments are complex and costly, they can be life-changing for the right patients. “Either of these approaches can significantly reduce the risk of acute pain episodes in 90 to 95 percent of patients,” Dr. Peslak notes. 

Clinical trial access at Penn Medicine

Access to the latest clinical trials is just one way that the Comprehensive Sickle Cell Program offers advanced care to patients. The program has a large team of providers, including social workers and mental health specialists who can help manage the burden of this lifelong illness. Those providers are also skilled at helping patients transition from pediatric to adult phases of care.

“Treatment for sickle cell disease can be very complex, and talking to a comprehensive program like the one here at Penn Medicine is critical,” Dr. Peslak says.

Referrals and consultations

Nadia Dawn Ali, MD, and Scott Alan Peslak, MD, PhD, see patients at the Penn Medicine Perelman Center for Advanced Medicine in Philadelphia, PA. For a provider-to-provider consultation with Dr. Ali or Dr. Peslak, please call 877-937-7366, or refer a patient online.