Primary immune deficiencies

Adenosine deaminase severe combined immunodeficiency (ADA-SCID)

Overview

ADA-SCID is a rare and life-threatening inherited disease of the immune system. Babies born with ADA-SCID have a faulty gene (the ADA gene).  Normally, this gene allows cells to build a protein called adenosine deaminase (ADA). When this protein is missing, the body cannot make a sufficient number of white blood cells (the cells in the blood that are responsible for fighting off infections). As a consequence, patients tend to have repeated and severe infections. If ADA-SCID is not treated properly, life expectancy can be very poor. ADA-SCID occurs in fewer than 1 in 200,000 births. 

Treating ADA-SCID

ADA-SCID can be treated in several ways. For example, patients can receive regular infusions of ADA protein. This requires weekly injections. Although this can help initially, over the long-term children remain at risk of life-threatening infections. Another way of treating ADA-SCID is by using a bone marrow or cord blood transplant when a suitable donor is available. This means that the patient with ADA-SCID receives stem cells, usually from the marrow of a healthy person. From these transplants stem cells, white blood cells can develop which will contain the functional ADA protein. If a matching donor is found, ideally a close family member, bone marrow or cord blood transplants can be very successful. However, when the donor is not a close enough match, there can be severe complications where the donor stem cells perceive the body of the patient as “foreign” and attack it.

Our approach

Doctors and scientists have invented a potential new way of treating ADA-SCID called "ex vivo autologous gene therapy". This involves making a copy of the normal gene in the laboratory and inserting it into a sample of the patient’s own blood or bone marrow stem cells, using a modified virus which carries the normal gene. This means that the stem cells now have a working copy of the missing gene (that is, the ADA gene). These genetically modified stem cells are then given back to the patient (the procedure is referred to as a “hematopoietic stem cell transplant”). After the stem cells are given back to the patient, they can grow and divide into new and functioning white cells that are able to fight off infections. One key advantage of "ex vivo autologous gene therapy” is that it uses the patient’s own cells (rather than a donor’s), so there is no chance that these cells attack the patient’s body or that the cells are rejected by the patient’s body.

Strimvelis®: EMA-approved ex vivo autologous gammaretroviral gene therapy

The treatment is available at the Ospedale San Raffaele in Milan, Italy. For more information, please contact a healthcare professional.

Strimvelis® has not been approved by the FDA.

OTL-101: ex vivo autologous lentiviral gene therapy in clinical development for ADA-SCID

Orchard is developing OTL-101, ex vivo autologous lentiviral gene therapy for ADA-SCID. For more information, please contact a healthcare professional.

Selected OTL-101 bibliography

Manuscript bibliography:

  1. Carbonaro DA, Zhang L, Jin X et al. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014 Mar;22(3):607-622. 

Congress bibliography:

  1. Kohn DB, Shaw KL, Garabedian E et al. Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID). Poster presented at: the 2019 Transplantation and Cellular Therapy (TCT) Meeting, the combined annual meeting of the American Society of Blood and Marrow Transplantation (ASBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR); February, 2019; Houston, TX. Abstract LBA12.
  2. Gaspar HB, Buckland K, Carbonaro D et al. Immunological and metabolic correction after lentiviral vector gene therapy for ADA deficiency. Mol Ther. 2015;23(Suppl 1):S102-3.
  3. Gaspar HB, Buckland K, Rivat C et al. Immunological and metabolic correction after lentiviral vector mediated haematopoietic stem cell gene therapy for ADA deficiency. Mol Ther. 2014;22(Suppl 1):S106.
  4. Kohn DB. Gene therapy for Primary Immune Deficiencies: ADA SCID and XCGD. Human Gene Ther. 2016; 27(11);A17.
  5. Kohn DB, Shaw KL, Garabedian E et al. Gene therapy for adenosine deaminase-deficient severe combined immunodeficiency (ADA SCID) with a lentiviral vector. J Clin Immunol. 2018;38(3):365.
  6. Kohn DB, Shaw KL, Garabedian EK et al. Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency. J Clin Immunol. 2019;39(Suppl 1);Abs 69.
  7. Kohn DB, Shaw KL, Garabedian EK et al. Autologous Ex Vivo Lentiviral Gene Therapy for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency Improves B Cell Function. J Clin Immunol. 2019;39(Suppl 1);Abs 70.

Wiskott-Aldrich syndrome (WAS)

Overview

Wiskott–Aldrich syndrome (WAS) is a rare and life-threatening inherited disease of the immune system. It occurs in approximately one baby in 200,000 births and affects boys almost exclusively. Babies born with WAS have a faulty gene that builds a protein called Wiskott–Aldrich protein (WASp). As a result, the number of platelets (the cells that are responsible for helping the body to form blood clots) is low and immune system cells (the cells in the blood that are responsible for fighting off infections) do not function normally. This means that patients with WAS are at risk of having bleeds, which can be very serious and life-threatening infections. In addition, some patients experience so called “autoimmune manifestations” (that is, the body attacks itself), severe eczema and cancers such as leukaemia or lymphoma.

Treating WAS

WAS can be treated in several ways. For example, doctors can attempt to prevent and manage symptoms of the disease with medicines to fight infections (such as antibiotics and immunoglobulin). This method is generally successful at preventing minor infections, but sometimes it is not able to combat severe infections. In addition, patients are given platelet infusions to prevent excessive bleeding. Another way of treating WAS is by using a bone marrow or cord blood transplant, when a suitable donor is available. This means that the patient with WAS receives stem cells from a healthy person. These normal stem cells will replace the defective ones and build a normal immune system and platelets to prevent infections and bleeds. If a matching donor is found, ideally a close family member, bone marrow or cord blood transplants can be very successful. However, when the donor is not a close enough match, there can be severe complications where the donor stem cells perceive the body of the patient as "foreign" and attack it.

Our approach

Doctors and scientists have invented a potential new way of treating WAS called "ex vivo autologous gene therapy". This involves making a copy of the normal gene in the laboratory and inserting it into a sample of the patient’s own blood or bone marrow stem cells, using a modified virus that carries the normal gene. This means that the stem cells now have a working copy of the missing gene (that is, the WAS gene). These genetically modified stem cells are then given back to the patient (the procedure is referred to as “hematopoietic stem cell transplant”). After the stem cells are given back to the patient, they can grow and divide into new and functioning white cells and platelets that are able to fight off infections and prevent bleeding. One of the features of "ex vivo autologous gene therapy" is that it uses the patient’s own cells (rather than a donor’s), so there is no chance that these cells attack the patient’s body or that the cells are rejected by the patient’s body.

OTL-103: ex vivo autologous lentiviral gene therapy in clinical development for WAS

Orchard is developing OTL-103, ex vivo autologous lentiviral gene therapy for WAS. For more information, please contact a healthcare professional.

Selected WAS bibliography

Manuscript bibliography:

  1. Aiuti A, Biasco L, Scaramuzza S et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013 Aug 23;341(6148):1233151. 
  2. Biasco L, Pellin D, Scala S et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell. 2016 Jul 7;19(1):107-19.
  3. Brigida I, Scaramuzza S, Lazarevic D et al. A novel genomic inversion in Wiskott-Aldrich-associated autoinflammation. J Allergy Clin Immunol. 2016 Aug;138(2):619-622.
  4. Castiello MC, Scaramuzza S, Pala F et al. B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2015 Sep;136(3):692-702.
  5. Ferrua F, Cicalese MP, Galimberti S et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 2019 May;6(5):e239-e253.
  6. Marangoni F, Bosticardo M, Charrier S, et al. Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models. Mol Ther. 2009 Jun;17(6):1073-82.
  7. Pala F, Morbach H, Castiello MC et al. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest. 2015 Oct 1;125(10):3941-51.
  8. Scala S, Basso-Ricci L, Dionisio F, et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells afterautologous transplantation in humans. Nat Med. 2018 Nov; 24(11):1683-1690.
  9. Sereni L, Castiello MC, Di Silvestre D et al. Lentiviral gene therapy corrects platelet phenotype and function in Wiskott-Aldrich patients. J Allergy Clin Immunol. 2019 Mar 26. [epub ahead of print].

Congress bibliography:

  1. Castiello MC, Bosticardo M, Scaramuzza S, et al. B Cell Reconstitution After Lentiviral Vector-Mediated Gene Therapy in Wiskott-Aldrich Syndrome Patients. Mol Ther. 2014;22(Suppl 1);S108.
  2. Castiello MC, Pala F, Morbach H, et al. Lentiviral-Mediated Gene Therapy Restores B Cell Homeostasis and Tolerance in Wiskott-Aldrich Syndrome Patients. Mol Ther. 2016;26(Suppl 1);S112.
  3. Ferrua F, Cicalese MP, Galimberti S, et al. Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome. Blood. 2015;126(23);259.
  4. Scaramuzza S, Ferrua F, Castiella MC, et al. Gene Therapy with Lentiviral Vector Transduced CD34+ Cells for the Treatment of Wiskott-Aldrich Syndrome. Mol Ther. 2011; 19(Suppl 1):S231.
  5. Scaramuzza S, Giannelli S, Ferrua F, et al. Persistent Multilineage Engraftment and WASP Restored Expression After Lentiviral Mediated CD34+ Cells Gene Therapy for the Treatment of Wiskott-Aldrich Syndrome. Mol Ther. 2014;22(Suppl 1);S88.
  6. Sereni L, Castiello MC, Ferrua F et al. Restoration of PLT structure and function in Wiskott-Aldrich syndrome patients after gene therapy treatment. Mol Ther. 2018;26(5S1);25-6.
  7. Sereni L, Catiello MC, Di Silvestre DD et al. Lentiviral Gene Therapy Corrects Platelet Phenotype and Function in Wiskott-Aldrich Patients. J Clin Immunol. 2019;39(Suppl 1);Abs 129.

X-linked chronic granulomatous disease (X-CGD)

Overview

X-linked chronic granulomatous disease (or X-CGD) is a rare and life-threatening inherited disease of the immune system. It occurs in approximately one baby in 100,000 to 200,000 births and affects boys almost exclusively. Babies born with X-CGD have a faulty gene (the CYBB gene). As a result, the white blood cells (the cells in the blood that are responsible for fighting off infections) are unable to kill bacteria and fungi. This leads to repeated chronic infections, especially in the lung, and abscesses in organs such as the liver. It is estimated that around 40% of patients with X-CGD will die by 35 years of age (source: Van den Berg 2009).

Treating X-CGD

X-CGD is managed in several ways. For example, doctors can attempt to prevent and manage symptoms of the disease with medicines to fight infections (such as antibiotics antifungal medicines). This method is generally not successful in preventing severe infections. Another way of treating X-CGD is by using a bone marrow or cord blood transplant, when a suitable donor is available. This means that the patient with X-CGD receives white blood cells from a healthy person. These white blood cells are able to kill bacteria and fungi. If a matching donor is found, ideally a close family member, bone marrow or cord blood transplants can be very successful. However, when the donor is not a close enough match, there can be severe complications where the donor stem cells perceive the body of the patient as "foreign" and attack it.

Our approach

Doctors and scientists have invented a potential new way of treating X-CGD called "ex vivo autologous gene therapy". This involves making a copy of the normal gene in the laboratory and inserting it into a sample of the patient’s own blood or bone marrow stem cells, using a modified virus that carries the normal gene. This means that the stem cells now have a working copy of the missing gene CYBB gene. These genetically modified stem cells are then given back to the patient (the procedure is referred to as “hematopoietic stem cell transplant”). After the stem cells are given back to the patient, they can grow and divide into new and functioning white blood cells which can fight off infections. One of the features of "ex vivo autologous gene therapy" is that it uses the patient’s own cells (rather than a donor’s), so there is no chance that these cells attack the patient’s body or that the cells are rejected by the patient’s body.

OTL-102: ex vivo autologous lentiviral gene therapy in clinical development for X-CGD

Orchard is developing OTL-102, ex vivo autologous lentiviral gene therapy for X-CGD. For more information, please contact a healthcare professional.

Selected X-CGD bibliography