Cell Therapies and Ultra-Rare Diseases

Cellular therapies offer the promise of treatments, and possibly cures, for a range of genetic diseases, particularly within hematopoietic (blood) cells.  However, many of these diseases are ultra-rare, meaning that fewer than 1 in 50,000 people are affected. At these low patient numbers, there are effectively no industry partners interested in out-licensing and developing these therapies commercially.  

Furthermore, developing therapies for ultra-rare diseases is hampered by the current regulatory frameworks which are not designed to address the challenges associated with approving drugs for such small patient populations.  The FDA and global regulatory agencies recognize that this is an issue and are slowly making inroads to address the problems.  Working with academic organizations to find long-term solutions for maintaining access has the potential to keep these treatments available to patients.

Without the potential of commercial partners, there are challenges in bringing our highly-effective therapeutics for ultra-rare diseases into standard of care once clinical testing is completed.  UCSF faculty, Mort Cowan, MD, and Jennifer Puck, MD, have developed a highly effective, paradigm changing hematopoietic stem cell (HSC) therapy for babies born with Artemis-deficient, severe-combined immunodeficiency (ART-SCID), an ultra-rare condition (fewer than five US/Canadian patients born per year) in which babies are born without a functioning adaptive immune system.  These babies lack T cells and B cells which are essential for not only fighting bacterial, viral and fungal infections but also for surveillance against emerging cancers.

Babies with ART-SCID, unfortunately, are not good candidates for the standard of care therapy, a bone marrow transplant (BMT) using a healthy donor’s (allogeneic) bone marrow hematopoietic stem cells.  The Artemis protein, an essential component of DNA repair, is non-functional in these babies, making them significantly more susceptible to ionizing radiation and alkylating chemotherapy, commonly used to prepare patients for an allogeneic BMT.  These babies also have an increased risk BMT rejection and are more likely to experience graft-vs-host disease (GVHD), a reaction that occurs when donor T cells react against tissue antigens in the recipient.  Dr. Cowan’s and Puck’s ART-SCID cellular gene therapy corrects the gene defect in the patients’ own blood forming hematopoietic stem cells, eliminating the need for an allogeneic BMT and consequently eliminating rejection, GVHD and long-term consequences from high-dose chemotherapy.

Artemis-deficient SCID, if left untreated, is fatal in infancy.  Prior to the ART-SCID cellular therapy, the survival rate among affected babies using standard of care treatment (allogeneic BMT) was around 60% and in 90% of the surviving children the immune system did not fully reconstitute unless high dose chemotherapy was administered.  However, the patients receiving high-dose alkylating chemotherapy had poor survival and if they did survive, were subjected to significant late effects and poor quality of life.  By comparison, to date in the ART-SCID cellular gene therapy clinical trial, the survival rate has been 100% with >85% of the treated children achieving complete or near complete immune reconstitution.  While it is still too early to tell, the ART-SCID cellular gene therapy has the promise of curing these young patients.  UCSF is working to keep this therapy available for those who need it.