Interview with Jennifer Puck, UCSF

Jennifer Puck earned her undergraduate and medical degrees at Harvard University and Harvard Medical School, after which she completed training in pediatrics, infectious diseases and immunology at Washington University in St. Louis and Baylor College of Medicine. After serving on the faculties of the University of Pennsylvania and the National Human Genome Research Institute of the National Institutes of Health, she joined UC San Francisco in 2006 as professor of pediatrics. Read her full bio.

Interview with Jennifer Puck, UCSF

Q: Severe combined immunodeficiency (SCID) is characterized by severely impaired T-cell development and is fatal without treatment. What is the current treatment of infants identified as having SCID, and what is their likely clinical outcome if treated shortly after birth?

A: • Overall, with improvements in bone marrow transplant protocols and supportive care, an unrelated bone marrow donor registry with >20 million volunteers signed up (for the large majority of SCID infants who lack an HLA matched sibling donor), and particularly with newborn screening to identify SCID cases early in life, clinical outcomes from allogeneic hematopoietic cell transplantation, the predominant treatment, have improved since 2000 and now exceed 90%. While survival is excellent, not all patients are completely immune reconstituted with some requiring immunoglobulin infusions because of incomplete ability to make protective antibody responses on their own.
• We have learned that SCID is not a single disease, but instead there are over 15 different genes that when mutated lead to SCID (and additional genes not yet identified). Also different mutations may produce completely null phenotypes or allow partially functional gene products to be made, so disease manifestations can vary, influencing treatment choices and outcomes. Some of the genes are expressed in tissues outside the immune system, and mutations in these have effects beyond causing immune deficiency. SCID due to some gene defects, such as X-linked IL2RG, have excellent survival while it is much less good in others such as the DNA repair gene Artemis (DCLRE1C).
• Individualized treatments according to a patient’s specific gene and mutation may improve survival and outcome further. Gene therapy has been developed for 3 genotypes of SCID, and appears to offer superior immune reconstitution as well as freedom from graft vs. host disease.

Q: You developed the T-cell receptor excision circle (TREC) newborn screening test for SCID. California instituted population-wide screening for SCID in August 2010 following pilot programs in Wisconsin, Massachusetts, and the Navajo Reservation. What were the results of the screening program in California and the outcomes of infants who were identified?

A: • We recently published results of 7.5 years of screening 3.25 million infants in California for SCID using the TREC test (Amatuni et al, Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California, 2010-2017. Pediatrics 2019;143(2): pii: e20182300. doi: 10.1542/peds.2018-2300. PMID: 30683812. 50 infants with SCID were discovered and promptly treated with 94% survival; and 4 additional infants were found to have complete DiGeorge syndrome treated with thymus transplants.
• SCID newborn screening is now part of routine newborn screening in all 50 states in the USA and is also being adopted in many countries worldwide.

Q: You published in April in the prestigious NEJM the results of a breakthrough experimental gene therapy in infants diagnosed with X-linked SCID that experts view as game-changer. Can you please tell us about the study and the results?

A: Addition of a correct copy of a SCID gene to the hematopoietic (blood-forming) stem cells isolated from a patient can restore immune function. These cells are removed from the body, transduced with a correct cDNA encoding the relevant gene and re-infused into the patient. Over the last 20 years protocols have evolved, overcoming initial challenges of (i) inability to produce sufficient normal protein to improve clinical status, and (ii) safety issues with first generation vectors associated with leukemia. The current lentivirus vector, combined with targeted, low-dose chemotherapy to open niches in the bone marrow for corrected stem cells, appears to be safe and effective at producing reconstitution of both T cell and B cell immunity. The collaborative study with St. Jude Children’s Research Hospital and UCSF has used this treatment successfully in infants with X-linked SCID, including those identified by newborn screening.

Q: What do you think is the future of SCID newborn screening and treatment in the coming 5-10 years?

A: • SCID newborn screening will be adopted widely and will enable affected infants to be identified and treated early. Non-SCID immune disorders are also important to detect early, but without a very sensitive and specific biomarker like TRECs to assay population-wide screening will be challenging. Deep sequencing of infant dried blood spots may eventually be done, but at this point variant interpretation is limiting, along with high cost and turnaround time.
• Inherited disorders of the hematopoietic system are outstanding targets for gene therapy because hematopoietic stem cells can be isolated, corrected ex vivo and reinfused. Graft vs. host disease and finding matched donors for transplants will no longer be limiting. SCID has led the way in this field and more genotypes of SCID will be treatable by gene therapy, but diseases such as sickle cell disease and thalassemia are also proving treatable by this means.
• Gene therapy will move from experimental clinical trials to standard of care; this is already happening.
• Gene editing may become a clinically useful method of gene therapy, offering advantages over gene addition.