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.

Ten young children born without functioning immune systems and lacking the ability to fight infections are on track for healthier lives thanks to a new gene therapy treatment. Ten young children born without functioning immune systems and lacking the ability to fight infections are on track for healthier lives thanks to a new gene therapy treatment pioneered at UC San Francisco, reports a Dec. 22 study in the New England Journal of Medicine. The children have Artemis-SCID, a very rare genetic disorder that is typically treated with a bone marrow transplant from a healthy donor, ideally a matched brother or sister. The new gene therapy allows researchers to treat newly diagnosed babies with their own cells -- adding a healthy copy of the Artemis gene to the baby's harvested marrow stem cells, then infusing the corrected stem cells back into their bodies -- in hopes of avoiding many of the short- and long-term complications of the standard treatment, including death. The children in the trial -- all under the age of 5 -- are living at home with their families, attending daycare and preschool, playing outside, and living normal lives, said Mort Cowan, MD, UCSF pediatrics professor and the trial's lead investigator. "Already, the course of their illness is so much better than with the typical treatment," said Cowan, who has treated more than 30 children with Artemis-SCID using standard bone marrow transplants. "I've never seen results like this in any of the other kids. It's amazing." Gene correction has been used before in patients with other genetic forms of SCID, but its use in Artemis-SCID is significant because these patients usually respond more poorly to standard bone marrow transplants. Complications can include rejecting the marrow graft, graft-vs.-host disease -- in which the donor T cells attack the recipient's tissues -- chronic infections leading to organ damage, stunted growth, and premature death. Signs of Stronger Immunity The first outcome of the Phase I/II trial involved the safe transfusion of gene-corrected cells that would differentiate into white blood cells by 42 days after infusion. Researchers theorized patients would need less chemotherapy to prepare their marrow for transfusion when their own cells were being used; thus only 25% of a full dose of busulfan was administered. The second outcome was T-cell reconstitution at 12 months, a measurement of the strength of the immune system. All 10 patients were safely transfused with their own gene-corrected stem cells that gave rise to corrected peripheral blood cells within 42 days. All 10 were growing their own T cells and B cells by 12 weeks, and four of nine (excluding a patient who received a second treatment) achieved full T-cell immune reconstitution by 12 months. Four of nine also achieved full B cell immunity by 24 months, allowing them to discontinue immunoglobulin replacement and receive standard childhood vaccinations. An additional three patients, who were followed for fewer than 24 months, had promising B cell development when compared to previous outcomes for donor-transplanted patients. One child required a second infusion of gene-corrected bone marrow due to a persistent infection with cytomegalovirus prior to gene therapy but is now infection free with good T- and B-cell immunity. "All of the results are better than those previously seen with Artemis-SCID patients who received donor bone marrow transplants," noted Jennifer Puck, MD, UCSF pediatrics professor and co-lead investigator in the study. "Having patients in the trial achieve full T-cell immunity is outstanding. B-cell recovery takes longer, but so far it looks as if the patients also have a far better chance for B-cell reconstitution than they would with a regular bone marrow transplant," Puck said. "Successfully using less chemotherapy is also a big win, minimizing the harmful side effects of full dose busulfan in small infants." Better B-cell immunity could help avoid issues such as chronic lung disease that often develop later in childhood for Artemis-SCID patients who receive a standard bone marrow transplant, Cowan added. The children in the trial are currently between the ages of 18 months and 4.5 years; nine were born in the U.S. and were diagnosed following newborn screening for SCID; one was born in Canada and diagnosed at five months of age with clinical illness. Four patients are of Navajo/Apache Native American descent, where the Artemis-SCID mutation is more common. Median follow-up was 31.2 months. At the time of study publication, six patients had been followed for at least 24 months. "We're pioneering gene therapy in this very rare disease right now, but we are using techniques that can be exported to other situations and can help many other conditions worldwide," said Puck. "Every new innovation happens one patient at a time." Co-authors: Also contributing to this research from UCSF were: Jason Yu, PhD; Carol Fraser-Browne, BA; Ukina Sanford, MS; Misako Kawahara, BA; Wendy Chan, BS; Shivali Chag, MS; and Robert Currier, PhD, of the UCSF Department of Pediatrics; Jess Oh, MS, of the UCSF Benioff Children's Hospital San Francisco; Jasmeen Dara, MD; Janelle Facchino, NP; Christopher Dvorak, MD, of the UCSF Department of Pediatrics and UCSF Benioff Children's Hospital San Francisco; Joan Hilton, DSc, MPH, of the UCSF Department of Epidemiology and Biostatistics; and Janel Long-Boyle, PharmD, PhD, of UCSF's Department of Pediatrics, School of Pharmacy and UCSF Benioff Children's Hospital San Francisco. Please refer to the paper for additional co-authors.