Emerging treatments

Emerging treatments

The recent European Medicines Agency (EMA) approval of the novel ex vivo gamma-retroviral gene therapy is a key milestone for progress in adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) treatment. The field of genome editing is rapidly progressing providing exciting new options with higher efficacy and improved safety.


Viral vector platforms

Additional research into the gamma-retroviral method of gene delivery further supports the use of this treatment in clinical practice, such as a phase II trial using the MND-ADA gamma-retroviral vector. The results demonstrated an excellent safety profile with no vector-related adverse events and, at the time of the reported results, nine of the 10 patients met the end point of intervention-free survival (Shaw, et al., 2017; see Table 1).

There has also been a development of newer generations of vectors, such as the lentiviral vector, with the potential to offer benefits such as the ability to transduce non-dividing as well as dividing cells. The use of an internal mammalian promoter offers a potential safety advantage. In light of this, on-going phase I/II clinical trials in the UK and US are investigating self-inactivating HIV-1-based lentiviral vectors in ADA-SCID patients (see Table 1).

Initial results from two parallel phase I/II trials in London and Los Angeles, reported on clinical data from 32 ADA-SCID patients treated with lentiviral vector-mediated gene therapy. The treatment was well tolerated with evidence of immunological and metabolic recovery in 31 of 32 patients treated for longer than 6 months (Gaspar, et al., 2015; Gaspar, ESID presentation, October 2016). Importantly, there was also no evidence of mutagenesis at the time of the published results, a recurrent safety concern associated with vector insertion. These initial results together with strong safety profiles demonstrated in other primary immunodeficiency conditions (Aiuti, 2013; De Ravin, 2016) suggest that lentiviral vectors are a viable option for use in autologous stem cell gene therapy.

Table 1: Clinical trials investigating viral vectors in ADA-SCID


Gene editing technology

There is still a need for improved control on vector site integration and gene-editing techniques, such as engineered endonucleases, are attracting attention for this purpose. They can work to disrupt and turn off the defected gene, repair a gene mutation, or replace the defective gene with a new copy of the gene (Kohn & Kuo, 2017).

Throughout the development of endonucleases, there has been a repeated concern of off-target mutagenesis caused by DNA breaks occurring at points other than the target site. Nonetheless, pre-clinical studies for primary immunodeficiency disorders, including ADA-SCID, have shown levels of safety and efficacy that may support advancement into the clinical setting (Lombardo, et al., 2007) (Joglekar, et al., 2013; Genovese, 2014). Positive results have also been shown in a clinical setting with HIV patients using ZFNs (Tebas, et al., 2014).

There is still some work to do to reduce the risk of off-target mutagenesis, but gene editing technology is revealing exciting new paths for in situ treatment of ADA-SCID as well as many other diseases.


Non-genotoxic conditioning for HSCT

Hematopoietic stem cell transplantation (HSCT) remains the long-standing treatment of choice for ADA-SCID patients as, if successful, it can be curative. However the success rate of the procedure has been limited by co-morbidities. Advances in stem cell gene therapy have addressed the complication of graft versus host disease but the toxicities of conditioning can remain a barrier (Palchaudhuri, et al., 2016). Recent research has been looking at replacing the current non-selective cytotoxic drugs with non-chemotherapy approaches that specifically target HSCs and other haematopoietic cells in the bone marrow. This could provide a conditioning technique that not only minimises undesirable toxicity but also allows for immunological recovery post-treatment (Cowan, et al., 2017).

One such targeted agent showing promise is the immunotoxin targeting the CD45 antibody expressed in haematopoietic cells, CD45-saporin (SAP). Pre-clinical studies in immunocompetent mice have shown results of 93–94% stable chimerism and complete, multi-lineage engraftment achieved by a single treatment of CD45-SAP followed by bone marrow transplantation; a result that is comparable with that of the conventional total body irradiation (TBI). Importantly, in contrast to conventional treatment, CD45-SAP was significantly less toxic, demonstrated by the preservation of the bone marrow architecture as well as the faster recovery of myeloid, B and T cells in the blood (Palchaudhuri, et al., 2016).

Alongside advances in gene editing strategies, these low-toxicity and targeted conditioning strategies have the potential to significantly expand the accessibility of stem cell transplantation to those who cannot currently tolerate the typical conditioning techniques.


Other developments

Polyethylene glycol recombinant adenosine deaminase (PEG-rADA) (ClinicalTrials.gov)

  • Aim: to replace purified natural bovine ADA with a recombinant source enzyme for the treatment of ADA-SCID
  • Demographic: patients currently receiving enzyme-replacement therapy (ERT) with pegylated purified natural bovine ADA who are not suitable candidates for bone marrow transplantation (BMT), or where BMT has failed
  • Development: phase III trials in the US and Japan; US FDA orphan drug status in March 2015


Written by Paul Taylor, Senior Medical Education Writer at Springer Healthcare IME, and reviewed and approved by Editorial Board Members, Andrew Gennery and Robbert Bredius.



Aiuti A., B. L. (2013). Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science, 1233151.

B.Gaspar, H., Buckland, K., A.Carbonaro, D., Shaw, K., Barman, P., Davila, A., et al. (2015). C-8. Immunological and Metabolic Correction After Lentiviral Vector Gene Therapy for ADA Deficiency. Molecular Therapy, S102-S103.

Bruin, L. M., Volpi, S., & Musunuru, K. (2015). Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies. Front Immunol., 250.

Candotti, F., Shaw, K. L., Muul, L., Carbonaro, D., Sokolic, R., Choi, C., et al. (2012). Gene therapy for adenosine deaminase–deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood, 120(18), 3635-3646.

Chhabra, A., Ring, A. M., Weiskopf, K., Schnorr, P. J., Gordon, S., Le, A. C., et al. (2016). Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Science Translational Medicine, 351ra105.

ClinicalTrials.gov. (n.d.). EZN-2279 in Patients With ADA-SCID. Retrieved August 2017, from https://clinicaltrials.gov/ct2/show/NCT01420627

Cowan, M. J., Dvorak, C. C., & Long-Boyle, J. (2017). Opening Marrow Niches in Patients Undergoing Autologous Hematopoietic Stem Cell Gene Therapy . Hematol Oncol Clin N Am, https://doi.org/10.1016/j.hoc.2017.06.003.

Czechowicz, A., Kraft, D., Weissman, I. L., & Bhattacharya, D. (2007). Efficient Transplantation via Antibody-Based Clearance of Hematopoietic Stem Cell Niches. Science, 1296-1299.

De Ravin S.S., W. X.-O. (2016). Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci. Transl. Med., 335ra57.

Genovese, P. (2014). Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells. Nature, 235-240.

Igarashi, Y., Uchiyama, T., & Minegishi, T. (2017). Single Cell-Based Vector Tracing in Patients with ADA-SCID Treated with Stem Cell Gene Therapy. Mol Ther Methods Clin Dev, 8-16.

Joglekar, A. V., Hollis, R. P., Kuftinec, G., Senadheera, S., Chan, R., & Kohn, D. B. (2013). Integrase-defective Lentiviral Vectors as a Delivery Platform for Targeted Modification of Adenosine Deaminase Locus. Molecular Therapy, 1705-1717.

Kohn, D. (2016). A Phase II/III Clinical Trial of Gene Therapy for ADA-Deficient SCID. Retrieved August 2017, from http://grantome.com/grant/NIH/U01-AI122260-01#panel-abstract

Kohn, D. (2017) Autologous Cryopreserved CD34+ Hematopoietic Cells Transduced With EFS-ADA Lentivirus for ADA SCID Retrieved August 2017, from https://clinicaltrials.gov/ct2/show/NCT02999984

Kohn, D. B., & Kuo, C. Y. (2017). New frontiers in the therapy of primary immunodeficiency: From gene addition to gene editing. Mechanisms of allergic diseases, 726-732.

Lombardo, A., Genovese, P., Beausejour, C. M., Colleoni, S., Lee, Y.-L., Kim, K. A., et al. (2007). Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nature Biotechnology, 1298 – 1306.

Palchaudhuri, R., Saez, B., Hoggart, J., Schajnovitz, A., Sykes, D. B., Tate, T. A., et al. (2016). Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nature Biotechnology, 738–745.

Shaw, K. L., Garabedian, E., Mishra, S., Barman, P., Davila, A., Carbonaro, D., et al. (2017). Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency. J Clin Invest, 1689-1699.

Tebas, P., Stein, D., Tang, W. W., Frank, I., Wang, S. Q., Lee, G., et al. (2014). Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. N Engl J Med, 901-910.


Share This: