Athabaskan Severe Combined Immunodeficiency

The collaboration’s initial focus is on developing gene-editing therapies for two rare genetic disorders. CRISPR pioneer Jennifer Doudna, Ph.D., looks set to continue to push the boundaries of gene editing, as she announces plans to team up with life sciences giant Danaher to create a center focused on generating new therapies for rare and other diseases. The center, which will be based at the headquarters of Doudna’s own Innovative Genomics Institute (IGI) and referred to as the Danaher-IGI Beacon for CRISPR Cures, “aims to use CRISPR-based gene editing to permanently address hundreds of diseases with a unified research, development and regulatory approach,” according to a Jan. 9 release from Danaher. Doudna will oversee the center’s work alongside Fyodor Urnov, Ph.D., Doudna’s fellow Berkeley professor who is also the IGI's Director of Technology and Translation. From its side, Danaher has pledged to “make available an extensive collection of technologies and solutions for the manufacturing of CRISPR-based therapies, and will also work to develop new technologies and approaches intended to simplify and standardize preclinical and clinical development.” The collaboration counts as one of Danaher’s ‘beacons’ programs, which fund academic research aimed at innovative technology ranging from precision diagnostics to biomanufacturing and data sciences. The collaboration with the IGI will be the largest beacon program to date, with Urnov appointed the beacon’s director. The collaboration’s initial focus is on developing gene-editing therapies for two rare genetic disorders: a life-threatening, hyper-inflammatory disorder called hemophagocytic lymphohistiocytosis; and Artemis-SCID, an immune deficiency that is typically treated with a bone marrow transplant. Both disorders are known as "inborn errors of immunity" (IEIs), which are thought to be particularly amendable to the Danaher/IGI approach, the company explained in the release. This is because the Danaher-IGI Beacon will have access to an extensive patient registry and offer a transplant-based route of administration that “bypasses some key challenges in delivering CRISPR molecules to appropriate tissues.” With around 500 diseases classified as IEIs, the center’s ultimate goal is for the resulting scalable platform to be used to rapidly create new therapies to treat many other disorders in this group as well as more common conditions that could be treated by editing a single gene. “Combining the strengths of the IGI and Danaher companies in this new center is a uniquely powerful way to deliver on the promise of CRISPR cures,” Doudna said in the release. “We know how to get CRISPR molecules into the tissues where they need to be. We know the patient communities. And we have the world experts on these diseases on our team,” she added. “What we need is a blueprint describing all the science and technology required to treat a person using CRISPR. Once that is achieved, I am convinced that CRISPR can become the standard of clinical care for many diseases."

Before her arrival, Stefanski was an associate professor of pediatrics at the University of Minnesota and was actively involved in clinical care and research involving children with life-threatening blood and immune system disorders. One of her areas of focus was the use of cord blood units in stem cell transplants and other cellular therapy. She is board certified in both Pediatrics and Pediatric Hematology-Oncology. In the last two decades, there has been a rapid evolution in the diagnosis and treatment of primary immunodeficiencies and the recognition of immune dysregulation, could you explain a) why this is and b) what point we are at currently with the diagnosis and treatment? ​ We are more sophisticated with our molecular techniques of detecting genes in these disorders.  There are approximately 500 inborn errors of immunity causing genes and with the widely available sequencing methods this number continues to grow rapidly. Established treatment options currently consist of immune modulatory drugs, antimicrobial prophylaxis, immunoglobulin replacement therapy and, allogeneic hematopoietic stem cell transplantation (HSCT) as well as gene therapy. Could you explain what causes inborn errors of immunity? ​ Inborn errors of immunity (IEI) are caused by genetic mutations. They can be x-linked, autosomal dominant or autosomal recessive.  They can also be novel mutations that are not inherited. IEI present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Until recently, management of treatment options were limited to prompt treatment of infections, gammaglobulin replacement and even bone marrow transplant depending on what was wrong. Could you outline the newer therapies including small molecule inhibitors, biologics, gene therapy etc? ​ In all types of gene therapy for IEI, ex vivo ​ gene therapy is used, in which a viral vector  is used to genetically modify cells from the patients with therapeutic intent. Gene editing can also be used where the DNA is repaired. Gene therapy has been used for multiple IEI including X-linked SCID, Artemis SCID, X-SCID, Wiskott-Aldrich Syndrome and Chronic Granulomatous Disease. What difference have these made to the patients? ​ These patients live longer, healthier lives and have a much better quality of life.  They are not hospitalized as frequently, they can attend school, they no longer need transfusions.  These therapies are life changing. What efforts have been made to increase awareness of IEI? ​ The advancement of genetic testing and diagnostic techniques have increased the awareness of IEI.  There are educational efforts to recruit young immunologists to the field as well as encouraging international collaborations. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) has also increased awareness.  These patients are identified immediately and have improved outcomes.  There are continual improvements and accessibility of genetic sequencing has accelerated identification of new IEI diseases. Advances and improvements in both gene therapy and hematopoietic stem cell transplant have made treatments possible in otherwise fatal diseases. Could you explain ‘newborn screening’ and the advantages or any disadvantages this may have? ​ Newborn screening identifies conditions that can affect a child’s long-term health or survival and is done within 24 hours after birth. Early detection, diagnosis, and intervention can prevent death or disability and enable children to reach their full potential.  The advantages are detecting life-threatening disorders early will impact that child’s health. Each year, new disorders, including IEI, can be detected on newborn screen.  The number of disorders detected varies by state. Where would you like to see this field in terms of development within the next decade or two? ​ A number of gene therapy trials using viral gene addition have been successful for ADA-SCID. Importantly, gene therapy approaches have become safer, more efficient and applicable to more IEI. Techniques for gene therapy continue to evolve and challenges include targeting the specific gene and minimizing the off-targets mutagenesis. The biggest obstacles remain cost and complex regulatory pieces. Where is the industry at with inborn errors of immunity? ​ We are continuing to improve gene therapy and expanding it to other IEIs.  We are making hematopoietic stem cell transplant safer for those that require transplant. The treatment for these disorders will change significantly in the next 10-20 years with more patients receiving gene therapy and additional IEIs being treated with gene therapy. We are truly on the cusp of novel therapies for these patients.