Development of a lentiviral gene therapy vector for treatment of haemophagocytic lymphohistiocytosis (HLH) due to perforin deficiency

Lead Research Organisation: University College London
Department Name: Institute of Child Health


HLH is a devastating disorder in which the immune system is unable to control infection and then becomes highly abnormal causing fever, enlargement of the liver and spleen and destruction of blood cells. The condition is caused by defects in certain genes and often affects children early in life. The only treatment is a bone marrow transplant which can be successful if a matched donor is available but is associated with significant complications if HLH is not controlled or if no good donor is available for transplant. To offer a safer and equally effective alternative, we want to use gene therapy to correct the condition. In early studies we have shown that if we introduce the perforin gene into bone marrow stem cells of perforin deficient mice and transplant them in perforin deficient recipients, we can restore the ability of the immune system to control infection and prevent HLH. These are very promising early data but to take this through to being a treatment for patients, we have perform a series of studies to show that it is both effective and safe.

We therefore plan to conduct a number of studies in different models of perforin deficiency with an optimal gene therapy vector that carries the perforin gene. We will correct bone marrow stem cells as previously but we will also challenge the corrected mice with a live infection to see if this prevents the onset of HLH. We will also also look at another approach and correct just blood (not bone marrow) immune cells as this may be a safer way of controlling disease.

Before taking this to patients, we also need to show that this treatment is safe. We will do this in a number of ways. We will show that once cells have been corrected, there is no evidence that they can then become cancerous because of the way the gene has ben inserted into the cells. We will also ensure that by introducing the gene into stem cells, this does not alter the function of the stem cell pool.

If we can show both effectiveness and safety in these studies, then this strategy can be taken forward for a clinical trial in HLH patients.

Technical Summary

HLH is a severe disorder of immune dysregulation characterized by failure of effector cell cytotoxicity in which affected individuals suffer multiorgan complications due to hypercytokinemia and histiocytic infiltration. Mutations in the perforin gene give rise to the most common form of HLH. Treatment of this disease is currently limited to the control of infectious triggers and chemotherapeutic regimes to control the initial dysregulation, but permanent correction can only be achieved by allogeneic hematopoietic stem cell (HSC) transplantation which has high mortality in mismatched donor transplants. The aim of this project is to develop a safe and effective lentiviral gene therapy vector encoding the perforin gene that can be used to modify autologous HSCs for treatment of perforin deficient HLH or to modify effector T and NK cells to be used to control disease activity in patients refractory to conventional chemotherapy. Initial experiments show that introduction of the correct copy of the perforin gene into HSCs can restore the T and NK cell defects seen in perforin deficient mice and that reconstituted mice are protected against development of HLH after viral challenge. These initial experiments provide a proof of principle for this gene therapy approach and pave the way for further studies to make this a clinical reality. We now seek further funding to undertake translational studies to develop and test a lentiviral vector that can be used in a Phase I/II clinical trial. We need to test the immunotoxicity and genotoxicity of this system and test whether the efficacy is long term and robust. A successful outcome will be data that confirms vector safety and efficacy and allow us to generate a clinical grade vector for use in clinical studies. This will be the first clinical gene therapy study for this group of disorders and extends the applicability of gene therapy for diseases of the haematopoietic system.

Planned Impact

If successful in this and future clinical trials, the research will have impact upon

1) Patients and their families - who will have an safe and effective treatment option for their disease
2) Clinicians dealing with the disease - who will now be able to have a further treatment option
3) The NHS - which will benefit from a treatment option that is economically more beneficial than current standard options and safer than allogeneic BMT
4) Biotech companies interested in vector manufacture - who may see learn from the techniques used to generate a high quality clinical grade lentiviral vector for clinical use
5) Industrial partners - who may see the vector and treatment as a possible commercial opportunity

This study adds to a growing body of work showing that gene and cell therapies can be genuine standard treatments in the future. This is also an area in which the UK are world leaders and so the this may be an opportunity for government or private investment. This will allow us to build our biotechnology capacity and expertise in the field of gene of cell therapies.


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Booth C (2014) Gene therapy for haemophagocytic lymphohistiocytosis. in Current gene therapy

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Carmo M (2015) Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency. in Molecular therapy : the journal of the American Society of Gene Therapy

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Ghosh S (2017) Gene Therapy Approaches to Immunodeficiency. in Hematology/oncology clinics of North America

Description H2020 project - RECOMB 
Organisation Leiden University Medical Center
Department Immunology (LUMC-I)
Country Netherlands 
Sector Hospitals 
PI Contribution Know how in ex vivo gene therapy
Collaborator Contribution Details on transduction of haematopoietic stem cells
Impact None so far
Start Year 2018
Description HLH gene therapy development 
Organisation Cincinnati Children's Hospital Medical Center
Country United States 
Sector Hospitals 
Collaborator Contribution RESEARCH COLLABORATION
Start Year 2011
Company Name Orchard Therapeutics 
Description Ex vivo bone marrow gene therapy company 
Year Established 2016 
Impact none so far but intention to take gene therapy developments to licensed medicines
Description Royal Society Christmas lecture 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Invitation to Royal Society Lecture to talk about gene therapy
Year(s) Of Engagement Activity 2018