No Alternatives: Why are Therapeutics Still Lagging for Sickle Cell Disease?

For Melisa Ruiz-Gutierrez, MD, the heartache comes as soon as she sees the hopeful eyes of parents cradling their newborn infant in their arms. It is her difficult task to explain their child’s sickle cell disease (SCD) diagnosis, to explain how pervasive the genetic blood disorder will be in their lives and the life of their new baby.

“Not only does the disease affect every organ of their body, but it will have an impact on every aspect of their lives. It affects school; it affects play; it affects their growth and development. Having these conversations with parents and having to say that we have only one medicine that we can give their infant to ameliorate some of the side effects of the disease is very heart-breaking,” explains Ruiz-Gutierrez, a pediatric hematologist and medical oncologist at Boston Medical Center.

For almost 40 years, one medicine, hydroxyurea, has remained the primary treatment for sickle cell disease. It is not a cure, however, only helping to reduce the hallmark sickling of red blood cells caused by a mutation in the hemoglobin gene. Treatment with hydroxyurea requires blood draws every three months, and constant monitoring and adjusting and does not work for every patient. When the drug is not effective, people are relegated to monthly blood transfusions to prevent the unbearable pain of acute sickle cell crises and the constant risk of debilitating strokes that lead to disability and shortened life expectancy.

Sickle cell disease, a recessive inherited disorder, primarily affects people of African descent. It has been documented since the early twentieth century and is considered the most prevalent monogenetic disease in the world. Yet, for a condition that affects millions globally, there have been too few breakthroughs in treatments. Over the past five years, three new therapies have been FDA approved for treatment of SCD, but only one is approved to treat children younger than 12. In comparison, another recessive genetic disease, cystic fibrosis (CF), affects primarily people of Caucasian descent. CF affects far fewer Americans (30,000 compared to 100,000 Americans with SCD), yet receives seven to 11 times the research funding per patient. The result is that 15 FDA-approved therapies are currently available on the market for CF.

Differences between the diseases’ expression and progression in the body do not explain this considerable disparity treatment, says Ruiz-Gutierrez. Structural racism in the United States has left generation after generation of African Americans and people of color in cycles of poverty. Priority has not been given to fund research for a disease seen as unprofitable and in a minority population left with little voice to advocate. Experts argue this historical neglect has left sickle cell disease patients suffering too long.

“There has never been a lack of dedicated scientists who are working hard to understand the impact of sickle cell disease. Research into understanding hemoglobinopathies has always been ongoing. Still, if there had been more funding for therapeutics earlier, we would be in a much different place now,” laments Ruiz Gutierrez.

This atrocity is finally being remedied. The development of new therapeutics for SCD is accelerating thanks to recent breakthroughs in understanding blood cell development and the advent of induced pluripotent stem cells (iPSCs) to study disease pathology.

The Center of Excellence in Sickle Cell Disease at BMC has partnered with the Center for Regenerative Medicine (CReM) to build the most extensive stem cell library for sickle cell disease in the world.

“Sickle cell disease is an incredibly complex disease. Even though people may have the same mutation that leads to the disease, there is this incredible diversity in the disease’s expression in the patient population, and that’s complex. It’s a major challenge,” explains George Murphy, Ph.D., a molecular and stem cell biologist who leads the stem cell library initiative at the CReM.

The library is housing stem cell lines that represent the genetic diversity of sickle cell disease, hastening the ability to test viable therapeutics—both genetic modifying technology and small molecule drugs—that can address the variety of disease expression within populations. Using iPSCs, scientists can replicate any cell or tissue type in a petri dish and test a therapy’s efficacy, crucial for breakthroughs in a progressive, systemic disease such as sickle cell disease. The CReM is committed to practicing “open-source” biology, freely sharing reagents, tools, vectors, cell lines and protocols with researchers around the world in the effort to speed discovery.

Cutting-edge gene therapies that modify blood cells to produce more functional hemoglobin show incredible promise to cure SCD. The technology is exciting and has improved parity in funding for the long-neglected disease. However, Murphy spends late nights worrying how these miracle cures will be made accessible for low-resource communities, not only in America but for the millions with sickle cell disease in Africa and the Caribbean.

“It will be very difficult to import these expensive and technical gene therapies into low-resource settings. However, there are emerging small molecule drugs, some of which may augment hemoglobin expression and others that may treat other aspects of the disease, such as vaso occlusion, that will be more accessible. Our laboratory is agnostic in that it can test these gene-editing therapies and also these more promising drugs that can be available more widely. These drugs can be potentially cheaper and more accessible, which can fill the gap until gene-based therapies are reduced in cost,” he says.

That is Murphy’s view on his optimistic days. Still, he acknowledges that for actual change to come to the sickle cell community, all parties scientific, governmental, philanthropic, insurance and pharmaceutical must come to the table to invest in bringing new, affordable drugs to the clinical stage and then to the public. During the nation’s greatest reckoning on race, the time to unite to end sickle cell disease is now.