Heal thyself: The promise of autologous hematopoietic stem cell gene therapy in neurometabolic disorders
Authors: Rebecca C. Ahrens-Nicklas
Journal: Molecular Therapy (2022)

Over the past three decades, the number of approved therapies for patients with inborn errors of metabolism (IEMs), especially lysosomal storage diseases (LSDs), has grown rapidly. Unfortunately, most approved treatments do not improve neurologic symptoms, even though most patients suffer from a severe burden of central nervous system (CNS) disease. To address this large unmet need, brain-directed gene therapy strategies are under development for many IEMs. In fact, as of June 2021, there were more than 30 completed or ongoing gene therapy trials targeting the CNS in LSDs.1Sevin C. Deiva K. Clinical trials for gene therapy in lysosomal diseases with CNS involvement.Front. Mol. Biosci. 2021; 8: 624988https://doi.org/10.3389/fmolb.2021.624988Google Scholar Most recently, an evaluation of atidarsagene autotemcel (arsa-cel) safety, efficacy, and durability by Fumagalli et al.2Fumagalli F. Calbi V. Natali Sora M.G. Sessa M. Baldoli C. Rancoita P.M.V. Ciotti F. Sarzana M. Fraschini M. Zambon A.A. et al.Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access.Lancet. 2022; 399: 372-383https://doi.org/10.1016/S0140-6736(21)02017-1Google Scholar expands upon promising results from an initial cohort. The study combines results from a larger open-label Phase I/II study and expanded access program. The study population comprised 29 early-onset (late-infantile and early-juvenile) patients with a mean duration of follow-up of approximately 3 years. Both the safety and efficacy results demonstrate the promise of this therapeutic approach in metachromatic leukodystrophy (MLD). The development of lentiviral hematopoietic stem-cell gene therapy (HSCT-GT) for MLD has been an early success story. This progressive metabolic leukodystrophy and LSD arises from pathogenic variants in ARSA, which encodes arylsulfatase A, a key cellular sulfatase. Loss of ARSA activity leads to the progressive accumulation of sulfatides in the nervous system, triggering demyelination and neurodegeneration. There is a broad spectrum of MLD severity, with late-infantile cases presenting before 30 months of age as opposed to juvenile cases that present after this age. In 2020, the European Medicines Agency (EMA) approved arsa-cel, a gene therapy comprising autologous hematopoietic stem and precursor cells transduced ex vivo with a lentiviral vector encoding human ARSA, for the treatment of pre-symptomatic late-infantile or early-juvenile MLD, or early-symptomatic early-juvenile MLD. This approval was based on a positive Phase I/II trial in 9 MLD patients.3Sessa M. Lorioli L. Fumagalli F. Acquati S. Redaelli D. Baldoli C. Canale S. Lopez I.D. Morena F. Calabria A. et al.Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial.Lancet. 2016; 388: 476-487https://doi.org/10.1016/S0140-6736(16)30374-9Google Scholar This initial cohort demonstrated improved biochemical markers of disease and neurologic outcomes as compared to untreated natural history controls. However, this study was limited in both size and duration of follow-up. In terms of efficacy, the new study by Fumagalli et al. met the coprimary endpoints of (1) biochemical improvement (i.e. an increase in peripheral blood mononuclear cell [PBMC] activity at 2 years post-transplant), and (2) functional improvement (i.e. an improvement of more than 10% in gross motor function measure [GMFM] as compared to natural history controls). Outcomes far exceeded these predetermined cutoffs, with PBMC ARSA activity levels reaching greater than 18-fold higher levels in infantile MLD patients as compared to pretreatment levels. Also, importantly, in the cerebrospinal fluid, ARSA activity levels improved from undetectable to the normal range. These biochemical improvements were sustained, even beyond 5 years post-transplant in the earliest-treated subjects. The subjects had impressive functional improvement as compared to natural history controls, with more than a 70% increase in GMFM score at 3 years in early-infantile patients. Practically, this means that 92% of treated late-infantile patients were able to at least sit without support at age 4.5 years as compared to 0% of natural history controls. A total of 88% were able to walk at the last available clinical evaluation. Not only were motor skills maintained but most patients also maintained performance and verbal IQs in the normal range. The therapy clearly improved neurologic outcomes when administered to pre-symptomatic patients. It is important to note that among early symptomatic early-juvenile patients, there were 2 deaths at 8 and 15 months after transplant due to rapid progression of disease, thought to be unrelated to therapy. This highlights the necessity for early diagnosis and treatment to optimize patient outcomes. Overall, arsa-cel therapy demonstrated a favorable safety profile. Study-related adverse events were generally related to complications of the busulfan-conditioning regimen, including febrile neutropenia, stomatitis, veno-occlusive disease, and thromobotic microangiopathy. The rates of conditioning-associated morbidity were consistent with reported rates among pediatric patients undergoing HSCT for metabolic disorders. In contrast to reported mortality rates of approximately 10% in patients with IEM undergoing standard HSCT,4Boelens J.J. Orchard P.J. Wynn R.F. Transplantation in inborn errors of metabolism: current considerations and future perspectives.Br. J. Haematol. 2014; 167: 293-303https://doi.org/10.1111/bjh.13059Google Scholar there were no transplant-related deaths. Reduced mortality was in part due to the use of autologous transplant, so subjects did not develop graft-versus-host disease or other complications of allogenic transplant. In addition, transplant mortality rates are strongly influenced by the experience of the transplant center. The study investigators had a high level of transplant expertise, which likely contributed to the excellent outcomes. It will be important to evaluate transplant-related morbidity and mortality rates in the real-world clinical setting as ex vivo gene therapy products become more widely prescribed. In addition to transplant-related complications, the lentiviral vector and transgene are also potential sources of morbidity and mortality. In terms of transgene response, 14% of patients developed anti-ARSA antibodies. All of the subjects had resolution of antibody response, with no clinical effects noted. A significant concern of ex vivo gene therapy is the oncogenic risk of the integrating lentivirus. Indeed, multiple cases of myelodysplastic syndrome (MDS) have occurred in a Phase III trial of ex vivo lentiviral gene therapy in patients with a different metabolic leukodystrophy, x-lined adrenoleukodystrophy.5Servick, K. (2021). Gene Therapy Clinical Trial Halted as Cancer Risk Surfaces. https://www.science.org/content/article/gene-therapy-clinical-trial-halted-cancer-risk-surfaces.Google Scholar Oncogenic potential is likely dependent on a number of specific vector features, but must be monitored for in all trials of lentiviral gene therapy. Subjects in the arsa-cel trial did not develop any signs of neoplastic transformation, and insertion site analysis showed a polyclonal pattern, without any signs of clonal dominance. An important caveat is that while an average of 3 years of follow-up in 29 subjects is large by rare disease standards, much more experience is needed to truly understand the cancer risk in this population. Ultimately, however, given the devastating nature of MLD and many other neurometabolic disorders, the risk of MDS or other neoplasm must be weighed against the potential benefit of lentiviral therapy in these progressive, devastating disorders. The promising data from ex vivo gene therapy trials in MLD have led to the clinical development of similar programs for other neurometabolic disorders. Marked improvement in neurologic outcomes have also been reported in x-linked adrenoleukodystrophy6Eichler F. Duncan C. Musolino P.L. Orchard P.J. De Oliveira S. Thrasher A.J. Armant M. Dansereau C. Lund T.C. Miller W.P. et al.Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy.N. Engl. J. Med. 2017; 377: 1630-1638https://doi.org/10.1056/NEJMoa1700554Google Scholar and mucopolysaccharidosis (MPS) type I7Gentner B. Tucci F. Galimberti S. Fumagalli F. De Pellegrin M. Silvani P. Camesasca C. Pontesilli S. Darin S. Ciotti F. et al.Hematopoietic stem- and progenitor-cell gene therapy for hurler syndrome.N. Engl. J. Med. 2021; 385: 1929-1940https://doi.org/10.1056/NEJMoa2106596Google Scholar trials. Positive results were also recently reported in patients with MPS IIIA and cystinosis (2022 Lysosomal WORLD Symposium). Collectively, these trials provide hope that autologous HSCT with gene therapy may both improve outcomes and minimize transplant-related complications. However, larger studies with longer follow-up periods are needed to fully elucidate both the potential risks and therapeutic benefits of this groundbreaking therapeutic approach. R.C.A.-N. has served as an advisor to Orchard Therapeutics on projects unrelated to MLD.