The FACTs trial for Fabry disease highlights the promise and challenges of gene therapy

Gene therapy studies in Fabry disease (FD) are proceeding utilising either lentivirus (LV) or adeno-associated virus (AAV) vectors with either ex vivo or in vivo transductions, respectively. In the FACTs (Fabry Disease Clinical Research and Therapeutics) gene therapy trial,1, 2 five male patients with classical FD (aged 29–48 years) received autologous LV-transduced CD34+ haematopoietic stem/progenitor cells (HSPCs). Cells were transduced ex vivo with a recombinant LV harbouring the cDNA for human α-galactosidase A (α-gal A) and returned to non-myeloablated hosts who had received low-dose melphalan. Cells engrafted well and polyclonal haematopoiesis was observed.3 In FD, as with a number of lysosomal storage disorders (LSDs), the overexpressed hydrolase can be used by primary corrected cells and can also be secreted, enabling uptake via a mannose-6-phosphate receptor into bystander cells. This was the rationale for targeting HSPCs as they, and their progeny, can circulate and thereby deliver the corrective enzyme systemically. In contrast to enzyme therapy (ET), this approach utilised a single infusion rather than continual biweekly treatments. This single infusion of LV-transduced cells led to continuous production of the α-gal A1 rather than variable peaks and troughs of activity as is seen with ET. The promise and challenges in gene therapy for amelioration of single-gene defects are highlighted by this study (See Figure 1). The 5-year data show that this LV-based gene therapy was safe and impactful.1 Four of the five patients went home the same day as their cell infusions. Febrile neutropenia was observed in one patient; another developed a PICC line infection. These were the only two severe adverse events. All patients achieved sufficient α-gal A activity that they technically did not have FD and were eligible to pause their ET. Three patients stopped ET and remained off for between 3 and 5 years duration. Other benefits were also observed: three of the patients had IgG-based antibody titres against α-gal A. In each case, these titres were reduced to background following the gene therapy and remained there for all 5 years. This was likely due to the conditioning regimen or to tolerisation generated by continual production of low levels of α-gal A from LV-transduced cells. Plasma globotriaosylsphingosine, an important biomarker, was also decreased in four of five patients. Further, estimated glomerular filtration rate, proteinuria and left ventricular mass index stabilised in most patients. After 5 years, no haematopoietic (or any other) malignancies have been seen in our study. This mirrors data to March 2022 in the entire gene therapy field when recombinant LV were employed.4 However, three recent trials contrast this situation.5 Haematological cancers developed in seven out of 67 patients total with cerebral leukodystrophy receiving autologous CD34+ HSPCs that had been transduced with a recombinant LV that engineered expression of the ABCD1 cDNA. That LV contained an internal MNDU3 promoter–enhancer; the FACTs study LV did not. These seeming outlier outcomes reinforce the need for in-depth testing of clinically directed LV constructs in a number of in vitro and in vivo assays6 prior to implementation. While this autologous approach epitomises ‘personalised medicine’, it also shows that individualised cell therapies, originating at different clinical sites and using centralised vector production and transduction locales, can still be effective given the complex logistics involved. Another important consideration is cost. The gene therapy in the FACTs study was performed at a significantly lower cost than other treatments for FD. The ET withdrawal in three Fabry patients saved the Canadian health care system over $4 M in ET costs over 5 years. The transduced cells were also infused in out-patient settings with only one patient requiring overnight hospitalisation. This contrasts the clinical and cost trajectories of gene therapy patients that receive full-dose busulfan myeloablative conditioning, for example. In summary, the safety results of the FACTs study, along with the durable and efficacious outcomes, opens the door for treatment of other LSDs that involve soluble lysosomal hydrolases. These results also make a compelling case for expanding the LV-mediated treatment of more FD patients including women and those with ‘non-classical’ disease. One challenge with a gene therapy like this is scale-up. How do you go from a trial involving five patients to treating many individuals with FD in such an effort-intensive adaptation of ‘personalised medicine’? Here, perhaps immunotherapies involving chimeric antigen receptor-modified cells would be a good model. LV-transduced T cells can also be used to deliver lysosomal hydrolases as we have shown.7 It would also be appealing to be able to treat many Fabry patients with a single ‘off-the-shelf’ approach. AAV is being explored in this context as it can be delivered systemically (LV virions are deactivated by human complement). Recombinant AAV integrates at a low frequency and can lead to fairly long-term expression of the transgene. However, a major problem with AAV is that many patients have pre-existing antibodies to common clinically used serotypes. AAV is also often administered in very high vector doses to achieve therapeutic outcomes, which can lead to toxicities and even death. AAV is often targeted to the liver but acute hepatotoxicity and delayed chronic liver damage have been seen.8 Another challenge in LSD gene therapy involves establishing the target enzyme activity that is needed to change clinical outcomes. Determining effective delivery of enzyme to non-transduced cells and organs involves biopsies and biomarker studies. While a persistent increase in enzyme activity may be achieved with gene therapy, it may only halt disease progression rather than be curative. In FD, some disease manifestations are not corrected by ET;9 it is unknown if gene therapy will do better. The FACTs LV-mediated gene therapy trial for FD showed that this approach is safe, efficacious and durable.1 In an effort to treat more patients the IP was licensed to a company. Unfortunately, the protocol was altered multiple times and the entire program was dropped. This was a severe blow to the FD community. A new company, Glafabra Therapeutics, Inc., has now been formed to raise money for additional LV-mediated gene therapy trials for FD and other amenable LSDs. Data sharing is not applicable to this article as no new data were created or analysed in this study.

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