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 "autologous ex vivo 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 “autologous ex vivo 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 autologous ex vivo gammaretroviral gene therapy

Strimvelis® is the first approved ex vivo gene therapy product, having received authorization by the European Medicines Agency in 2016. Strimvelis® is approved for the treatment of patients with ADA-SCID who do not have a suitably matched stem cell donor. 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.

Selected Strimvelis bibliography

Manuscript bibliography:

  1. Aiuti A, Cattaneo F, Galimberti S et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58.
  2. Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017 Jun;9(6):737-740.
  3. Biasco L, Scala S, Basso Ricci L et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med. 2015 Feb 4;7(273):273ra13. 
  4. Carriglio N, Klapwijk J, Hernandez RJ et al. Good laboratory practice preclinical safety studies for GSK2696273 (MLV vector-based ex vivo gene therapy for adenosine deaminase deficiency severe combined immunodeficiency) in NSG mice. Hum Gene Ther Clin Dev. 2017 Mar;28(1):17-27.
  5. Cicalese MP, Ferrua F, Castagnaro L et al. Gene therapy for adenosine deaminase deficiency: a comprehensive evaluation of short- and medium-term safety. Mol Ther. 2018 Mar 7;26(3):917-931. 
  6. Cicalese MP, Ferrua F, Castagnaro L et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016 Jul 7;128(1):45-54.
  7. Cockroft A, Cole B, Leacy S, Nord M. Challenges of registering an autologous cell-based gene therapy product. Regulatory Rapporteur 2017;14;9-13
  8. Ferrua F, Aiuti A. Twenty-five years of gene therapy for ADA-SCID: from bubble babies to an approved drug. Hum Gene Ther. 2017 Nov;28(11):972-981.
  9. Migliavacca M, Assanelli A, Ponzoni M et al. First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature. Front Immunol. 2018 Feb 2;9:113.
  10. Monaco L, Faccio L. Patient-driven search for rare disease therapies: the Fondazione Telethon success story and the strategy leading to Strimvelis. EMBO Mol Med. 2017 Mar;9(3):289-292. 
  11. Sauer AV, Hernandez RJ, Fumagalli F et al. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Sci Rep. 2017 Jan 11;7:40136.
  12. Scott O, Kim VH, Reid B et al. Long-term outcome of adenosine deaminase-deficient patients – a single-center experience. J Clin Immunol. 2017 Aug;37(6):582-591. 
  13. Stirnadel-Farrant H, Kudari M, Garman N et al. Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID. Orphanet J Rare Dis. 2018 Apr 6;13(1):49
  14. Tucci F, Calbi V, Barzaghi F, et al. Successful treatment with Harvoni® in an ADA-SCID infant with HCV infection allowed gene therapy with Strimvelis®. Hepatology. 2018 Jul 16. doi: 10.1002/hep.30160. [Epub ahead of print]

Congress bibliography:

  1. Bergemann R, Gaffuri A, Barrett J et al. ADA-SCID: qualitative assessment of caregiver perceptions of treatment options. Presentation at: 44th Annual Meeting of the European Society for Blood and Marrow Transplantation; March 18-21, 2018; Lisbon, Portugal. Abstract B056.
  2. Bergemann R, Mustchin E, Barrett J et al. ADA-SCID: the burden and impact on the patient, caregiver and family. A qualitative research in USA, Italy, France and UK. Poster presented at: International Primary Immunodeficiencies Congress: Focus on Diagnosis and Clinical Care; November 8-10, 2017; Dubai, UAE. Poster 8.
  3. Biasco L, Dionisio F, Pellin D, et al. Clonal Tracking of Engineered Hematopoiesis In Vivo in Humans By Insertional Barcoding. Mol Ther. 2015;23(Suppl 1);S189.
  4. Biasco L, Scala S, Basso Ricci L et al. Comprehensive clonal mapping of hematopoiesis in vivo in humans by retroviral vector insertional barcoding. Blood. 2014;124(21):5.
  5. Biasco L, Scala S, Cieri N et al. Clonal tracking of T-cell composition, fate and activity in vivo in humans. Mol Ther. 2014;22 (Suppl 1):S107-8. 
  6. Petrillo C, Cesana D, Piras F et al. Dissecting immunomodulatory relief of lentiviral restriction in human hematopoietic stem and progenitor cells for efficient gene transfer. Mol Ther. 2014;22 (Suppl 1):S205. 
  7. Gabaldo M, Ferrua F, Cicalese MP et al. Bringing an effective gene therapy to ADA-SCID patients: Strimvelis as a successful example of a collaborative effort involving a charity, a research hospital and a pharmaceutical company. Presented at: 3rd International Rare Diseases Research Consortium Conference; February 8-9, 2017; Paris, France. Abstract 16.
  8. Kotsopoulou N, Kirkpatrick A, Ward N, et al. Development of the manufacturing process for the ex vivo gene therapy for ADA-SCID (GSK2696273). Human Gene Therapy. 2013;24(12):A41.
  9. Kotsopoulou N, Kirkpatrick A, Ward N, et al. Development of the manufacturing process for the ex vivo gene therapy for ADA-SCID (GSK2696273): process design, validation and comparability. Human Gene Therapy. 2014;25(11):A44.
  10. Monaco L, Gabaldo M, Ferrua F et al. Strimvelis as a successful model for the development of accessible advanced therapies for ultra rare diseases. Poster presented at: 9th European Conference on Rare Disease & Orphan Products; May 10-12, 2018; Vienna, Austria. Poster 251.
  11. Scala S, Biasco L, Basso Ricci L et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Blood. 2014;124(21):547.
  12. Zonari E, Boccalatte F, Plati T et al. Genetic engineering and transplantation of highly purified hematopoietic stem cells (HSC) for improved ex vivo gene therapy. Mol Ther. 2014;22 (Suppl 1):S13. 

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

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

Selected OTL-101 bibliography

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 "autologous ex vivo 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 "autologous ex vivo 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: autologous ex vivo lentiviral gene therapy for WAS

Orchard is developing OTL-103, autologous ex vivo 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. 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.
  6. 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.
  7. 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 Oct 1. [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.

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 "autologous ex vivo 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 "autologous ex vivo 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: autologous ex vivo lentiviral gene therapy for X-CGD

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

Selected X-CGD bibliography