Hematopoietic Stem Cell Transplantation Therapy Research Articles

Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, plasma cytokine levels, and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective and kidney impairment was not improved in either model.

Thrombotic complications after hematopoietic stem cell transplantation and other cellular therapies

Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor-T (CAR-T) immunotherapy are widely used for the management of hematological malignancies. HSCT can be complicated by endothelial injury syndromes, such as HSCT-thrombotic microangiopathy (HSCT-TMA) and sinusoidal obstructive syndrome/veno-occlusive disease (SOS/VOD), which are life-threatening. Moreover, venous thromboembolic events (VTEs) are common in HSCT recipients due to endothelial injury, use of central venous catheters, prolonged hospitalization, and the development of a procoagulant state. VTEs have also been reported post-CAR-T infusion. The management of thrombotic events in these patients is challenging, due to the high risk of bleeding that is present. CAR-T immunotherapy might be followed by toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicity syndrome (ICANS). Endothelial dysfunction is implicated in the pathogenesis of these syndromes. Early recognition and management of the above complications are crucial for better patient outcomes.

Hematopoietic stem cell transplantation and cellular therapy in persons living with HIV.

Summarize the latest research of both stem cell transplantation and cellular therapy and present the implications with respect to persons with HIV (PWH), hematologic malignancies, and HIV-1 cure. Allogeneic (alloSCT) and autologous (autoSCT) stem cell transplantation have been shown to be well tolerated and effective regardless of HIV-1 status. AlloSCT leads to a decrease in the HIV-1 latently infected reservoir orders of magnitude below that achieved with antiretroviral therapy (ART) alone. Utilization of CCR5Δ2/Δ32 donors in an alloSCT has resulted in HIV-1 cures. In the last 12 months, three cases of cure have been published, giving further insight into the conditions required for HIV-1 control. Other advances in the treatment of hematological cancers include chimeric antigen receptor T-cell (CART) therapy, which are active in PWH with lymphoma. Here we discuss the advances in SCT and cellular therapy in PWH and cancer. Additionally, we discuss how these technologies are being utilized to achieve HIV-1 cure.

Enzymatic testing for mucopolysaccharidosis type I in Kuwaiti newborns: a preliminary study toward newborn screening.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder characterized by deficient or absent α-L-iduronidase (IDUA) enzyme activity due to pathogenic variants in the IDUA gene. Early treatment with hematopoietic stem cell transplantation and/or enzyme replacement therapy is associated with improved outcomes in this progressive multisystem disease. The diagnosis is usually delayed due to late presentation and non-specific symptoms, which result in high morbidity and mortality. The incidence of MPS I is unknown in Kuwait. This pilot study was undertaken to screen MPS I in all Kuwaiti neonates born at Farwaniya Hospital (FH), a major center in Kuwait, over 12 months. This study examined the incidence of MPS I for inclusion in the national newborn screening (NBS) to enable its early detection and adequate treatment. All Kuwaiti neonates born at FH between December 2021 and December 2022 were screened for MPS I. The screening consisted of determining IDUA enzyme activity in dried blood spot-derived samples using tandem mass spectrometry. A follow-up genetic analysis of the IDUA gene has been planned to screen the cases with diminished IDUA enzyme activity as second-tier testing. A total of 618 newborns, including 331 (54%) boys and 287 (46%) girls, were screened. Of them, 20 had deficient IDUA enzyme activity but showed negative genetic testing. However, we have diagnosed one additional female infant with MPS I who belonged to FH, but the parents chose to deliver in a private hospital. The molecular genetic study revealed the presence of a previously reported pathogenic nonsense variant in the IDUA c.1882C>T, which is associated with severe phenotype. That being included, MPS I is estimated to be approximately 0.2% of all screened cases in Kuwait. Our study is the first to evaluate the incidence of MPS I in Kuwait. Given the single center, small number of screened infants, and the short study duration thus far, it is premature to calculate the incidence. It is anticipated that as the study continues, we would be able to estimate the incidence in our population correctly. Screening newborns in all maternity hospitals in Kuwait is necessary to calculate the actual incidence of this severe disorder. Still, our preliminary data support the inclusion of MPS I in national NBS program to allow early initiation of treatment and thus improve disease outcome.

Preimplantation Genetic Testing for HLA Matching (PGT-HLA) When Only Partial Embryo Matches are Identified

Introduction: Preimplantation Genetic Testing (PGT) is an option for couples to select embryos that have a matching Human Leukocyte Antigen (HLA) type to a child that is in need of hematopoietic stem cell transplant (HSCT). Families in search of HLA-matched donors for HSCT may have a difficult time finding publicly available optimal donors or donors within their families. The likelihood of a family finding an optimal donor can vary from 16% to 75%, depending on ethnic and racial groups. Previously, PGT-HLA has been used to identify potential future siblings who would be an HLA match to an affected child through embryo testing as early as 2001 for conditions like Fanconi Anemia. PGT-HLA can be complicated by the presence of recombination within the HLA complex on chromosome 6 in the affected individual. If an affected child is found to be recombinant within the HLA complex (6-7% of PGT-HLA cases), the chances of finding a full sibling-matched donor can be extremely low. PGT for partial HLA matching can be used when the affected child is found to be recombinant or if a full parental match is not possible. When a child is identified as recombinant in the HLA region, consultation with their transplant team can determine whether a partial sibling match would be a good therapeutic candidate. PGT-HLA is performed by linkage analysis which requires DNA samples from the oocyte source, sperm source, and the affected child. These results will determine shared parental regions of the HLA complex genes so that partial matches can be identified. Case Reviews: We present two cases of PGT-HLA where only partial matches were identified during embryo testing. Of these 2 cases, both families completed one testing cycle for PGT-M and PGT-HLA and both had partial matches that were recommended for transfer per patient consent. One family had 3 partial match embryos, but they did not have a successful pregnancy following frozen embryo transfer. However, during the period of their transfers, they were able to find an adequate publicly-matched donor for HSCT therapy for their child. In one family, only a paternal HLA match was sought due to advanced maternal age of the mother. Consultation with the family’s transplant team indicated that a paternal-only match would be sufficient for a therapeutic effect. Conclusions: Despite the complexity of testing for PGT-HLA matching for a child where a full sibling match is not available embryo testing can still provide a therapeutic benefit. Interdisciplinary consultation in these cases would optimally include the couple, the affected child’s transplant team, the couple’s reproductive endocrinologist, and genetic counseling available at the PGT laboratory or the REI office. As accessibility to PGT continues to grow and as guidelines for PGT acceptability continue to be written, PGT-HLA should similarly find more usage. Inevitably, partial embryo matches will be seen and we will continue to learn how these can be used in clinical practice.

Patient engagement in hematopoietic stem cell transplantation and cell therapy: a survey by the EBMT patient engagement task force & transplantation complications working party.

The EBMT (European Blood and Marrow Transplantation Society) aims to connect patients, the scientific community, and other stakeholders to improve hematopoietic stem cell transplantation and cellular therapy outcomes. We performed a cross-sectional online survey to understand the perceptions regarding Patient Reported Outcomes (PROs) and Patient Active Involvement in Research (PAIR) in over 800 stakeholders (n = 813). Patients (n = 278) and health care professionals (HCPs) (n = 351) were compared. We observed high openness for EBMT PRO collection (n = 680, 84.5% across stakeholders' groups; patients n = 256, 93.1% versus HCPs n = 273, 78.4% [p < 0.001]) and PAIR (n = 702, 87.3% across stakeholder groups; patients n = 256, 92.4% versus HCPs n = 296, 85.8% [p = 0.009]), with a significantly higher proportion of patients expressing interest compared to HCPs. Priority domains for PROs data-collection identified were the assessment of symptom experience, psychosocial and cognitive functioning. The most important issues for patients specifically were the data-collection of PROs reflecting cognitive function, the option of reporting data at home, the importance of identifying actionable targets to improve their recovery, and receiving feedback on their input when participating in research projects. Our multistakeholder approach suggests an added value to embracing patient engagement in the development of meaningful research and service design within the transplantation and cellular therapy community.

Hematopoietic stem cell transplantation or enzyme replacement therapy in Gaucher disease type 3

Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1).All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1.We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression.

Optimization of a home hospitalization program for hematopoietic stem cell transplantation with ehealth integration and clinical pharmacist involvement.

Home hospitalization represents an alternative to traditional hospitalization, providing comparable clinical safety for hematological patients. At-home therapies can range from the delivery of intravenous antibiotics to more complex scenarios, such as the care during the early period after hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. Early discharge from conventional hospitalization is feasible and helps reduce hospital resources and waiting lists. The coordinated efforts of multidisciplinary teams, including hematologists, nurses, and pharmacists, ensure patient safety and continuity of care. The traditional model of home hospitalization relies on home visits and telephone consultations with physicians and nurses. However, the use of eHealth technologies, such as MY-Medula, can enhance communication and monitoring, and thereby improve patient outcomes with no additional costs. The active involvement of a clinical pharmacist in home hospitalization programs is essential, not only for the proper logistical management of the medication but also to ensure its appropriateness, optimize treatment, address queries from the team and patients, and promote adherence. In conclusion, the implementation of hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy home hospitalization programs that use both an eHealth tool and a multidisciplinary care model can optimize patient care and improve quality of life without increasing healthcare costs.

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: A Study on Behalf of the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy Group (GETH)

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed.

Real-World Experience with Isavuconazole in Allogeneic Stem Cell Transplantation in Spain

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile.

Brentuximab vedotin therapy followed by autologous peripheral stem cell transplantation as a viable treatment option for an older adult with transformed lymphoma: a case report and literature review.

This report presents a case involving a woman aged >65 years who had been diagnosed with marginal zone lymphoma 3 years prior. The patient was hospitalized with enlarged inguinal lymph nodes, and pathological examination revealed that the lymphoma had transformed into diffuse large B-cell lymphoma. After two cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP) chemotherapy, the patient achieved complete remission. This treatment was followed by autologous hematopoietic stem cell transplantation and lenalidomide maintenance therapy. At the last follow-up, the patient had been in continuous remission for 24 months. This case study suggests that the utilization of BV and R-CHP in conjunction can result in rapid remission, and it can be followed by autologous hematopoietic stem cell transplantation and maintenance therapy with lenalidomide. This treatment approach exhibits potential as a viable option for older individuals with transformed lymphoma.

Newborn screening for inborn errors of immunity: The status worldwide

BackgroundNewborn screening (NBS) for the early detection of inborn errors of immunity (IEI) has been implemented in a few countries. The objective of this study was to verify the situation and define obstacles to the implementation of NBS worldwide. MethodsA questionnaire was developed by the Inborn Errors of Immunity Committee of the World Allergy Organization (WAO) with 17 questions regarding NBS for IEI in the physician's workplace, NBS test type, problems hindering NBS implementation, reimbursement for IEI therapy, presence of a national IEI registry, referral centers, molecular diagnosis, hematopoietic stem cell transplantation centers, gene therapy, and immunoglobulin replacement therapy. The survey was sent by email once a week to doctors and others associated with WAO and the main immunology societies worldwide as a Google Form™ to be completed during September and October 2021. ResultsTwo hundred twenty-nine questionnaires were completed, of which 216 (94.3%) were completed by physicians. One hundred seventy-six (76.8%) physicians were both allergists and immunologists. The agreement between allergists/immunologists and non-allergists/non-immunologists for the question “Is there NBS for IEI in the country you work in?” was good (κ = 0,64: 95% CI 0.55–0.69). Ninety-eight (42.8%) participants were from Latin America, 35 (15.3%) from North America, 29 (12.6%) from Europe, 18 (7.9%) from Africa, 44 (19.2%) from Asia, and 5 (2.2%) from Oceania. More than half the participants (n = 124, 54.2%) regularly treated patients with IEI, followed by occasional treatment (n = 77, 33.6%), or never (n = 28, 12.2%). Of the respondents, 14.8% reported that their countries performed NBS for IEI, whereas 42.2% reported their countries did not. T-cell receptor excision circles was the most widely used technique in some countries, with 75 (59.9%) for the diagnosis of NBS for IEI, followed by combined use with kappa deleting-recombination excision circles. Only 13 participants (10.3%) underwent neonatal exon screening in their respective countries. Financial and technical issues were among the major obstacles to the implementation of NBS for IEI. ConclusionsThis pilot study showed that few countries have implemented NBS for IEI, despite the presence of immunology referral centers and the availability of hematopoietic stem cell transplantation and intravenous immunoglobulin replacement therapy. The findings highlight the difficulties, mainly financial and technical, hindering wide application of NBS. Sharing experiences, technologies, and resources at the international level can help overcome these difficulties.

The Evolution of Hematopoietic Stem Cell Transplantation to Overcome Access Disparities: The Role of NMDP.

NMDP recognizes that despite advances in hematopoietic stem cell transplantation (HSCT) and other cell therapies, not all patients have equitable access to treatment, and disparities in outcomes remain. This paper explores the recent work of NMDP to accelerate progress and expand access to more patients through transformative clinical research, particularly in the use of mismatched unrelated donors for HSCT.

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill.

Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.

Lysosomal storage diseases. Sphingolipidoses – leukodystrophy

Lysosomal storage diseases. Sphingolipidoses – leukodystrophy

Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency

PurposePatients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi.MethodsWe report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data.ResultsRevcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2–3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred.ConclusionRevcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.

Brave new world: expanding home care in stem cell transplantation and advanced therapies with new technologies.

Hematopoietic stem cell transplantation and cell therapies like CAR-T are costly, complex therapeutic procedures. Outpatient models, including at-home transplantation, have been developed, resulting in similar survival results, reduced costs, and increased patient satisfaction. The complexity and safety of the process can be addressed with various emerging technologies (artificial intelligence, wearable sensors, point-of-care analytical devices, drones, virtual assistants) that allow continuous patient monitoring and improved decision-making processes. Patients, caregivers, and staff can also benefit from improved training with simulation or virtual reality. However, many technical, operational, and above all, ethical concerns need to be addressed. Finally, outpatient or at-home hematopoietic transplantation or CAR-T therapy creates a different, integrated operative system that must be planned, designed, and carefully adapted to the patient's characteristics and distance from the hospital. Patients, clinicians, and their clinical environments can benefit from technically improved at-home transplantation.

One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival

AbstractWiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Anti-CD45 PBD-based antibody-drug conjugates are effective targeted conditioning agents for gene therapy and stem cell transplant

Stem cell gene therapy and hematopoietic stem cell transplantation (SCT) require conditioning to ablate the recipient's hematopoietic stem cells (HSCs) and create a niche for gene-corrected/donor HSCs. Conventional conditioning agents are non-specific, leading to off-target toxicities and resulting in significant morbidity and mortality. We developed tissue-specific anti-human CD45 antibody-drug conjugates (ADCs), using rat IgG2b anti-human CD45 antibody clones YTH24.5 and YTH54.12, conjugated to cytotoxic pyrrolobenzodiazepine (PBD) dimer payloads with cleavable (SG3249) or non-cleavable (SG3376) linkers. Invitro, these ADCs internalized to lysosomes for drug release, resulting in potent and specific killing of human CD45+ cells. In humanized NSG mice, the ADCs completely ablated human HSCs without toxicity to non-hematopoietic tissues, enabling successful engraftment of gene-modified autologous and allogeneic human HSCs. The ADCs also delayed leukemia onset and improved survival in CD45+ tumor models. These data provide proof of concept that conditioning with anti-human CD45-PBD ADCs allows engraftment of donor/gene-corrected HSCs with minimal toxicity to non-hematopoietic tissues. Our anti-CD45-PBDs or similar agents could potentially shift the paradigm in transplantation medicine that intensive chemo/radiotherapy is required for HSC engraftment after gene therapy and allogeneic SCT. Targeted conditioning both improve the safety and minimize late effects of these procedures, which would greatly increase their applicability.