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.

在一项新的临床研究中，来自美国加州大学旧金山分校的研究人员开创了一种新的基因疗法，有望让10名出生时没有功能性免疫系统、缺乏抗感染能力的幼童获得更健康的生活。 在一项新的临床研究中，来自美国加州大学旧金山分校的研究人员开创了一种新的基因疗法，有望让10名出生时没有功能性免疫系统、缺乏抗感染能力的幼童获得更健康的生活。相关研究结果发表在2022年12月22日的New England Journal of Medicine期刊上，论文标题为“Lentiviral Gene Therapy for Artemis-Deficient SCID”。 这些儿童患有Artemis缺陷型重症联合免疫缺陷（Artemis-SCID），这是一种非常罕见的遗传性疾病，通常用健康供者（最好是匹配的兄弟或姐妹）的骨髓移植来治疗。这种新的基因疗法使得科学家们能够用他们自己的细胞治疗新诊断的婴儿---将健康的Artemis基因拷贝添加到从患病婴儿体内收集的骨髓干细胞中，然后将经过校正后的骨髓干细胞输注回他们的身体，希望能避免标准治疗的许多短期和长期并发症，包括死亡。 论文通讯作者、加州大学旧金山分校儿科教授Mort Cowan博士说，这项临床试验中的患儿都在5岁以下，他们与家人一起生活在家里，参加日托和学前班，在外面玩耍，过着正常的生活。 Cowan之前已用标准的骨髓移植治疗了30多名Artemis-SCID儿童。Cowan说，“他们的病程已经比典型的治疗方法好得多。我从来没有在其他孩子身上看到过这样的结果。这很令人吃惊。” 基因校正以前已被用于治疗患有其他遗传形式的SCID的患者，但它在Artemis-SCID中的使用意义重大，因为这些患者通常对标准骨髓移植的反应较差。并发症可能包括骨髓移植物排斥；移植物抗宿主病，即供者的T细胞攻击接受者的组织；导致器官损伤的慢性感染；生长迟缓；过早死亡。 Laverna Shorty是2018年第一个报名参加这项临床试验的婴儿的祖母和护理人员，她看到她的孙子“HT”在最初几年经历了很多痛苦。HT的病情是在他在美国亚利桑那州出生后不久发现的，他被空运到加州大学旧金山分校进行治疗。 Shorty说，“HT出生时就患有Artemis-SCID，但在经历了这项临床试验后，他现在过着正常的生活。他不再生病了。他停止了所有的药物治疗。他很快乐，他正在成长为一个年轻人。” 更强免疫力的迹象 这项I/II期临床试验的第一个结果涉及安全输注经过基因校正的骨髓干细胞，这些干细胞在输注后42天内会分化成白细胞。这些作者推测，当患者使用他们自己的细胞时，他们需要更少的化疗来为血液输注做准备；因此，只需给送白消安（busulfan）的全剂量的25%。第二个结果是12个月时的T细胞重建，这是衡量免疫系统强度的一个标准。 所有10名患儿都被安全地输注了他们自己的经过基因校正的骨髓干细胞，在42天内产生了经过基因校正的外周血细胞。所有10名患儿到12周时都长出了自己的T细胞和B细胞，9名患儿中有4人（不包括一名接受第二次治疗的患儿）到12个月时实现了完全的T细胞免疫重建。9名患儿中有4人到24个月时也实现了完全的B细胞免疫，使他们能够停止免疫球蛋白替代，并接受标准的儿童疫苗接种。另外三名患儿，随访时间少于24个月，与之前接受供者骨髓移植的患儿的结果相比，他们的B细胞发育前景良好。 一名患儿由于在基因治疗前持续感染巨细胞病毒，需要第二次输注经过基因校正的骨髓干细胞，但如今已经没有感染，并具有良好的T细胞和B细胞免疫力。论文共同作者、加州大学旧金山分校儿科教授Jennifer Puck博士指出，“所有的结果都比以前接受供者骨髓移植的Artemis-SCID患儿的结果要好。” 图片来自New England Journal of Medicine, 2022, doi:10.1056/NEJMoa2206575。 Puck说，“让这项临床试验中的患儿获得完全的T细胞免疫力是非常出色的。B细胞恢复需要更长的时间，但目前看来，患儿的B细胞重建机会也远比常规的骨髓移植要好。成功地使用较少的化疗也是一个很大的胜利，最大限度地减少了较小婴儿的全剂量白消安的有害副作用。” Cowan补充说，更好的B细胞免疫力可能能够有助于避免接受标准骨髓移植的Artemis-SCID患儿在童年后期经常出现的慢性肺部疾病等问题。 这项临床试验中的患儿目前年龄在18个月至4.5岁之间；9名儿童在美国出生，在新生儿筛查SCID后被诊断；1名儿童在加拿大出生，在5个月大时被诊断出患有临床疾病。4名患儿是Artemis-SCID致病突变更为常见的纳瓦霍/阿帕奇美洲原住民（Navajo/Apache Native American）的后裔。随访的患儿中位数是31.2个月。在这项研究发表时，有6名患儿已经被随访了至少24个月。 Puck说，“我们如今在这种非常罕见的疾病中开创了一种基因疗法，但我们使用的技术可以应用到其他疾病，可以帮助治疗全世界许多其他疾病。每项新的创新都是在一名患者身上发生的。”（生物谷 Bioon.com） 参考资料： 1. Morton J. Cowan et al. Lentiviral Gene Therapy for Artemis-Deficient SCID. New England Journal of Medicine, 2022, doi:10.1056/NEJMoa2206575. 2. Sung-Yun Pai. Gene Therapy for Artemis-Deficient SCID. New England Journal of Medicine, 2022, doi:10.1056/NEJMe2213255. 3. Infant gene therapy is a breakthrough for Artemis-SCID patientshttps://medicalxpress.com/news/2022-12-infant-gene-therapy-breakthrough-artemis-scid.html