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DevelopIng Genetic medicines for Severe Combined Immunodeficiency (SCID)

Periodic Reporting for period 3 - SCIDNET (DevelopIng Genetic medicines for Severe Combined Immunodeficiency (SCID))

Reporting period: 2019-01-01 to 2019-12-31

Severe combined immunodeficiency (SCID) is a devastating rare disorder of immune system development.

SCID has been at the forefront of gene therapy development and was the first condition to be effectively cured by gene therapy worldwide, through trials initiated in Paris (INSERM), London (UCL) and Milan (OSR) (all SCIDNET Partners). Members of the SCIDNET consortium have worked together for 15 years developing and performing the first successful clinical trials of gene therapy worldwide for two forms of SCID (SCID-X1 and ADA SCID) and also for other immunodeficiency conditions.

The challenge now is to take these trial advances and move gene therapy from the academic arena into a licensed genetic medicine that can be used as a standard treatment for patients worldwide. The SCIDNET consortium will now work to commercialise gene therapy for ADA SCID as a licensed medicine and this is a major objective and ambition of this proposal.

Proof of concept of gene therapy for other SCID forms (RAG1/2 and Artemis deficiency) has also been shown by members of the SCIDNET consortium and is ready for translation into clinical trials. We are therefore in a position whereby, over the next 4 years, we can offer gene therapy as a curative option for 70% of all forms of SCID in Europe. Importantly for at least 1 of these conditions (ADA SCID) we will undertake clinical trials that will lead to potential marketing authorisation (MA) of the gene therapy product as a licensed medicine. The ADA SCID trial will act as a paradigm for the development of the technologies and manufacturing protocols and processes that will allow gene therapy for not only SCID, but also other bone marrow disorders, to become authorised genetic medicines in the future.

SCIDNET objectives are:

1. To deliver safe and effective gene therapy as a licensed medicine for children with SCID initially within Europe and then worldwide

2. To develop the expertise and manufacturing protocols that can be used for other rare genetic diseases of the bone marrow

3. To develop the new viral and gene editing technologies that will become future gene therapy medicines, to be used routinely globally

4. To undertake studies that have Orphan Drug Designation and intellectual property protection in order to attract commercial partnership and investment

5. To engage and involve SCID families and patient support groups to help design clinical studies and to keep patient/family stakeholders informed of scientific progress

6. To engage with EU regulatory agencies in order to achieve marketing authorization across the EU for ADA SCID gene therapy by the end of the project

7. To maintain and reinforce the European leadership in developing ex vivo gene therapy in general, and gene therapy for immunodeficiencies in particular
The lead study is ADA SCID gene therapy in which we proposed that during SCIDNET, we would undertake a cryopreserved formulation study that would provide the data together with compilation of data from a historical cohort for a marketing authorisation application with the EMA. This is now being taken forward with a commercial partner who is funding the study and is applying industrial standards for the conduct of the study and for data collection and analysis. The trial has now been approved and has recruited 9 patients.

Despite difficulties in making vector for SCID-X1 and Artemis clinical trials, a study of GT for SCIDX1 is now approved and open at UCL with the first patient having been treated. Artemis vector has been made and the necessary studies to open a trial are being undertaken.

With regard to the preclinical studies that encompass the majority of the other WPs of SCIDNET, these are progressing well and in some cases, faster than anticipated. In particular, the development of gene therapy for RAG1 has been very successful and has resulted in a successful H2020 application which will allow this study to also proceed to a clinical trial.

In other areas, MHH (partner nº 8) has been working on the alpha retroviral platform as an alternative vector system for treatment of SCID. They are focusing on the IL-7Ra SCID for which there have been no previous gene therapy development activities. This would provide yet another gene therapy option for another genetic form of SCID, although this is unlikely to enter clinical trial within the context of SCIDNET.
The scale of SCIDNET ambition is that this will not be restricted:
a) to the EU, but will build models and practices that can be used globally and
b) to SCID, but the methods and technologies developed will be transferable to other rare and also common bone marrow disorders.

For monogenic diseases of the bone marrow, gene therapy has the potential to be a permanently curative therapy through gene transfer into self-renewing HSCs. The major ambition is now to perform studies that allow marketing authorisation application. In SCIDNET we have the opportunity in the LV ADA SCID study, to bring to licence one of the first curative gene therapy medicines. In current trials, patients have had to travel to the treatment site with resulting disruption and costs to family and healthcare. Furthermore, the need to infuse freshly transduced cells restricts the amount of conditioning that can be given and also does not allow for full characterisation of the transduced cell product before it is infused into patients. Our strategy of shipping cells to a central site, freezing gene corrected cells and shipping the product back to the patient bedside anywhere in Europe and ultimately the world, is unprecedented for gene therapy and will result in highly novel procedures and protocols.

The technologies and protocols that we adopt for the ADA SCID study will act as a paradigm and template for other gene therapy trials that follow, initially LV SCID-X1 and Artemis that will be part of the SCIDNET programme, but also RAG1/2 that may come after SCIDNET. However, our ambition is that this can become standard practice for future bone marrow gene therapy studies not just for the immune system but for a large number of other rare metabolic diseases as well as the more common haemoglobinopathies.

Economic and commercial impact
Gene therapy for SCID will considerably reduce healthcare costs for the treatment of this condition and potentially many others. Gene therapy for SCID-X1 and ADA-SCID is undertaken with minimal chemotherapy and most patients have a limited hospital stay of approximately 4-5 weeks, thereby considerably reducing in-patient treatment costs in comparison to a 20 week average stay for patients undergoing a fully conditioned procedure.

In addition to the reduced inpatient stay costs which may reduce costs by as much as 50%, a successful ADA SCID gene therapy outcome means that patients can stop highly expensive enzyme replacement therapy (approximate cost €400,000 per patient per year). Similarly, autologous stem cell gene therapy has the potential to off-set ERT for a number of other monogenic metabolic lysosomal disorders. In these other conditions (see Table 4) such as MPS-I and Pompe disease. A one-off autologous stem cell gene therapy procedure can be curative and can negate the lifelong requirement for this form of replacement therapy.