September 12, 2024
“White Coats” is an AABB News series that interviews the experts that are transforming the fields of transfusion medicine and biotherapies. Join AABB today to read the rest of this month’s issue.
Akshay Sharma, MBBS, is a clinician-scientist in the department of bone marrow transplantation and cellular therapy at St. Jude Children’s Research Hospital in Memphis, Tenn. He graduated from medical school at Kasturba Medical College in Mangalore, India, then pursued a postdoctoral fellowship at Emory University. He then went on to complete a pediatrics residency at the University of Kentucky and a pediatric hematology-oncology fellowship at St. Jude Children’s Research Hospital. Sharma’s postdoctoral research focused on understanding the genetic regulation of fetal hemoglobin and his current clinical research continues to translate that work developing novel transplant and gene therapy clinical trials for patients with blood disorders. He leads several clinical trials of genetic and cellular therapies for non-malignant hematological disorders and is an expert in the development of novel gene editing therapeutics. Sharma is passionate about developing curative therapies for hemoglobinopathies, such as sickle cell disease (SCD), as well as improving access to these novel therapies in an equitable and patient-centered manner.
Both my parents are physicians, so I grew up surrounded by medical professionals and knew that I wanted to pursue a career in the sciences. Medical school was an easy and obvious choice given my early childhood exposure. After medical school, I wanted to take some time and experience basic science research, so I joined the laboratory of Dr. Edmund Waller at Emory University. His lab focused on tumor immunology and graft engineering, which exposed me to the field of hematopoietic cell transplantation. I learnt the basics of cell therapies in the lab, and soon realized how much we didn’t know – and that fascinated me! It’s the pursuit of the unknown, the adventure of developing something novel and impactful, that has fueled my passion in biotherapies. I have been incredibly fortunate to have so many dedicated mentors, and a very proud and supportive spouse without whom I would not have been where I am today. I owe it to all of them to help me have this fulfilling career.
I joined St. Jude as a clinical fellow in 2015. Even before I joined my pediatric hematology oncology fellowship, I knew I wanted to be a transplant physician. But I didn’t have a niche I wanted to specialize in. I wanted to spend some more time in the lab during my research years in the fellowship and was looking for lab mentors – which is when I met Dr. Mitch Weiss. His lab was studying genetic regulation of the globin switching and had identified a locus in the gamma-globin promoters that could be disrupted using CRISPR-Cas nuclease system to turn fetal hemoglobin back up again in adult red blood cells. His group wanted to study this further. This was at the beginning of the CRISPR revolution, when there were few people using this technology. When I graduated from the lab, I started translating this pre-clinical work into a clinical product that we can deliver to patients, and today I am leading a clinical trial (NCT06506461) doing just that.
The development of CRISPR-Cas based autologous hematopoietic cell therapies has been transformative for individuals with inherited disorders of the hematopoietic system. We are closer than ever to offering a potentially curative therapy to every person with a genetic blood disorder. With the advances in molecular genetics and our understanding of gene regulation, and the use of novel CRISPR-based technologies to influence a change on these regulatory mechanisms, we are now able to therapeutically change the instruction manual (the genetic code) of the blood cells. This has changed the field of cell therapy and transplantation forever.
I am sure you have heard people say, “we now have a cure for everyone with sickle cell disease.” Well, that’s not entirely true, but it’s close. We could potentially offer a one-time transformative treatment to everyone with SCD. Gene therapy has removed a lot of barriers that an allogeneic hematopoietic cell transplantation has – immunological complications, need for graft-versus-host disease prophylaxis, donor availability, etc. Although there are still a lot of challenges to implementation of gene therapy around the world – cost, accessibility, equity – we can overcome these with innovative strategies. In addition, several small molecules with novel mechanisms and pathways are being developed that could transform the natural history of SCD. When we are successful in making these therapies accessible to everyone who needs them throughout the world, we will have achieved a breakthrough in SCD.
Generally speaking, there aren’t enough well-trained professionals – apheresis nurses, medical technologists, scientists, nurses, clinicians and pharmacists, who are knowledgeable of the various aspects of the care of an individual with SCD and able to deliver such complicated therapies efficiently. Those who are working in the field are stretched thin and can only do so much. So, we first need to train and retain such a valuable workforce. But the elephant in the room is the issue of equitable access to these therapies. Two gene therapy products were approved in the U.S. and Europe in December 2023. They are available but remain inaccessible for most people who need them. The cost of these cellular drug products and the resources required to deliver them are out of reach for most people even in high-income countries, not to mention the high burden of SCD in low- and middle-income countries where most people with this disease live. We must do better to make these therapies accessible equitably, and that requires governmental commitment, political will, philanthropic support, interest from biotech and big pharma, better infrastructure and resources and, last but not least – buy-in of the patients we serve. These are all barriers that risk the successful implementation of the scientific successes we have made so far, but hopefully they are not unsurmountable.
To see my patients who have undergone these transformative therapies – gene therapy or bone marrow transplant for sickle cell disease – go from being hopeless about their future to being energetic, hopeful and excited fuels me. That’s what drives my work, with the dream that one day we can say that we truly have a cure for everyone (without any asterisks).
As we started treating patients with autologous genetic therapies, we really did not know what to expect in terms of post-infusion immune reconstitution. We extrapolated data from allogeneic hematopoietic cell transplants and autologous hematopoietic cell rescue after high dose chemotherapy (like we do for neuroblastoma and myeloma) and started monitoring patients for immune reconstitution after infusion. In the early days, we offered every recipient onerous antimicrobial prophylaxis to prevent opportunistic infections and often re-vaccinated everyone against vaccine preventable diseases a few months after infusion. But as we studied immune reconstitution (and in fact immune persistence), we noted that not only do these individuals retain a lot of their immune function, but it might also get better after undergoing gene therapy.
I am hopeful there will be advances in manufacturing of ex vivo gene therapies so that we can produce these products more efficiently and with little inconvenience to patients. Currently, it is a long and arduous process for them. I am also hoping that we can develop non-genotoxic conditioning agents so that patients don’t have to receive chemotherapy prior to administration of these genetic therapies. This will make the administration of these genetic therapies safer. Last but not least, the holy grail is to make the genetic modification process work in vivo. If we could just give patients one injection or infusion, that would correct or change the genetic code in their blood cells inside their bodies without having to go through apheresis and receive chemotherapy to make them SCD-free; that would be the goal we are all aiming for.
Being part of the pivotal clinical trial that led to the FDA approval of the world’s first CRISPR/Cas edited living medicine – exagamglogene autotemcel – has been one of the highlights of my professional career. But personally, I am much prouder of having had the privilege to take care of so many children and young adults with SCD – many of whom couldn’t plan their lives or careers due to the fear of experiencing unbearable pain all the time. Watching them go on to lead fullfilling, productive and happy lives, without the fear of experiencing pain or having to visit a hospital is my proudest accomplishment as a physician.
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