Neurometabolic disorders

Metachromatic leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is a rare, life-threatening inherited metabolic disorder. MLD is caused by a mutation in the ARSA (arylsulfatase-A) gene, leading to a deficiency in the ARSA enzyme, the accumulation of sulfatides and the progressive destruction of the myelin sheath in nerve cells. As a result, patients experience a progressive deterioration in their neurological and motor function. In the most common form of the disease, late-infantile MLD (~60% of MLD), symptoms are usually observed before the age of 3 years and mortality at 5 years is estimated at 75%. In juvenile MLD (~30% of MLD), symptoms are usually observed between the age of 3 and 16 years, and mortality at 5 years is estimated at 30% in this population (Mahmood 2010). In adult MLD (~10% of MLD), the onset of symptoms usually occurs from the age of 16 years. The incidence of MLD is currently estimated at approximately 1 in 100,000 live births, although it can vary depending on the geographical location (sources: Bonkowski 2010; Poupetova 2010; Lugowska 2011; Kehrer 2011; AL-Jasmi 2012; Stellitano 2016).

Currently, there are no effective treatments for MLD. Allogenic haematopoietic stem cell transplantation has limited efficacy in arresting disease progression and is therefore not considered as a standard of care. Palliative care involves medications for seizures and pain, antibiotics and sedatives, on a case-by-case basis, as well as physiotherapy, hydrotherapy and tube feeding or gastrostomy in the later stages of the disease. The impact of MLD on caregivers and families is considerable.

For more information:

Please contact medinfo@orchard-tx.com or visit clinicaltrials.gov to learn more about a study to assess safety and efficacy of OTL-200 for treatment of Metachromatic Leukodystrophy (MLD).

OTL-200: ex vivo autologous lentiviral gene therapy in clinical development for MLD

Orchard is developing OTL-200, ex vivo autologous lentiviral gene therapy for MLD. Data from the ongoing registrational study have been published in the Lancet in 2016. In this study, early treatment with OTL-200 in most asymptomatic patients has demonstrated preservation of cognitive and motor development to levels comparable with healthy individuals (source: Sessa 2016). The median follow-up period was 3 years (range 18–54 months). These results contrast with outcomes observed in the untreated siblings of the late infantile patients in the clinical study and in aged-matched historical controls, in whom gross motor function typically declines rapidly from the onset of symptoms leading to death in many cases by the age of 5 years. The treatment procedure was well tolerated, and no serious adverse events related to the medicinal product were reported.

OTL-200 was acquired from GSK in April 2018. Orchard is completing an ongoing clinical study with the cryopreserved formulation of OTL-200, while discussions with regulatory authorities continue in anticipation of a submission for a marketing authorization application with regulatory authorities.

Selected MLD bibliography

Manuscript bibliography:

  1. Biffi A, Capotondo A, Fasano S et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Invest. 2006 Nov;116(11):3070-82.
  2. Biffi A, De Palma M, Quattrini A et al. Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J Clin Invest. 2004 Apr;113(8):1118-29.
  3. Biffi A, Montini E, Lorioli L et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158.
  4. Calbi V, Fumagalli F, Consiglieri G et al. Use of Defibrotide to help prevent post-transplant endothelial injury in a genetically predisposed infant with metachromatic leukodystrophy undergoing hematopoietic stem cell gene therapy. Bone Marrow Transplant. 2018 Jul;53(7):913-917.
  5. Cesani M, Plati T, Lorioli L, et al. Shedding of clinical-grade lentiviral vectors is not detected in a gene therapy setting. Gene Ther. 2015 Jun;22(6):496-502.
  6. Penati R, Fumagalli F, Calbi V, et al. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. J Inherit Metab Dis. 2017 Jul;40(4):543-554
  7. Sessa M, Lorioli L,Fumagalli F et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016 Jul 30;388(10043):476-87. 

Congress bibliography:

  1. Biffi A, Bartolomae CC, Cesana D et al. Lentiviral vector common integration sites in the ALD and MLD clinical trials and in a preclinical model reflect a benign integration bias and not oncogenic selection. Mol Ther. 2011;19(Suppl 1):S234.
  2. Calabria A, Spinozzi G, Randoita P, et al. Characterization of Hematopoietic System Reconstitution In Vivo in Metachromatic Leukodystrophy Gene Therapy Patients. Mol Ther. 2019;27(4S1):Abs 693.
  3. Calbi V. Update on safety and efficacy of HSC gene-therapy for metachromatic leukodystrophy. Bone Marrow Transplantation. 2017(52);S17–S115.
  4. Calbi V, Fumagalli F, Penati R, et al. Defibrotide (DF) prophylaxis and adjustment of busulfanschedule to prevent veno-occlusive disease and thrombotic microangiopathy in an infant with a membrane cofactor protein (MCP) gene mutation and Metachromatic Leukodystrophy undergoing Hematopoietic Stem Cell (HSC-GT) Gene Therapy. Bone Marrow Transplantation. 2017(52);S124–S516.
  5. Calabria A, Spinozzi G, Merelli I, et al. Molecular characterization of hematopoietic system reconstitution in metachromatic leukodystrophy patients following hematopoietic stem cell gene therapy. Mol Ther. 2018;26(5S1):312.
  6. Calabria A, Spinozzi G, Merelli I, et al. Molecular characterization of hematopoietic system reconstitution in 7 metachromatic leukodystrophy patients following hematopoietic stem cell gene therapy. Mol Ther. 2017;25(5S1):15.
  7. Fumagalli F, Calbi V, Zambon A, et al. Update on safety and efficacy of lentiviral hematopoietic stem cell gene therapy (HSC-GT) for metachromatic leukodystrophy (MLD). Eur J Paed Neurol. 2017;21(Suppl 1):e20.
  8. Fumagalli F, Calbi V, Sessa M, et al. Lentiviral hematopoietic stem cell gene therapy (hsc-gt) for metachromatic leukodystrophy (MLD) provides sustained clinical benefit. Bone Marrow Transplant. 2019;54(16-141):O094.
  9. Fumagalli F, Calbi V, Sessa M, et al. Lentiviral hematopoietic stem cell gene therapy (hsc-gt) for metachromatic leukodystrophy (mld) provides sustained clinical benefit. Presented at: 2019 Annual Clinical Genetics Meeting sponsored by American College of Medical Genetics and Genomics (ACMG); April 2-6, 2019; Seattle, WA, USA.
  10. Scifo P, Della Rosa PA, Canini M, et al. Quantitative 1H single voxel spectroscopy in metachromatic leukodystrophy patients treated with haematopoietic stem cell gene therapy: preliminary results. Poster presented at: International Society for Magnetic Resonance in Medicine Annual Meeting; June 16-21, 2018; Paris, France. Abstract 5421.
 

Mucopolysaccharidosis type I (MPS-I)

Mucopolysaccharidosis type I (MPS-I) is a rare inherited neurometabolic disease caused by a deficiency of the IDUA (alpha-L-iduronidase) lysosomal enzyme needed to break down glycosaminoglycans (also known as GAGs or mucopolysaccharides). The accumulation of GAGs across multiple organ systems results in the symptoms of MPS-I including neurocognitive impairment, skeletal deformity, loss of vision and hearing, hydrocephalus, and cardiovascular and pulmonary complications. MPS-I occurs at an overall estimated frequency of approximately one in every 100,000 live births. There are three subtypes of MPS-I; approximately 60 percent of MPS-I patients have the severe Hurler subtype, which when untreated results in patients rarely living past the age of 10.

Treatment options for MPS-I include bone marrow transplant and chronic enzyme replacement therapy, both of which have significant limitations. Though early intervention with enzyme replacement therapy has been shown to delay or prevent some clinical features of the condition, it has only limited efficacy on neurological symptoms.

OTL-203: ex vivo autologous lentiviral gene therapy in clinical development for MPS-I

Orchard is developing OTL-203, ex vivo autologous lentiviral gene therapy for MPS-I. Orchard was granted an exclusive worldwide license to intellectual property rights to research, develop, manufacture and commercialize the ex vivo autologous hematopoietic stem cell (HSC) gene therapy program for the treatment of MPS-I developed by the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. OTL-203 is the only ex vivo autologous HSC program currently in clinical development.

The program has shown encouraging preliminary data with signs of metabolic correction in patients with the most severe subtype of MPS-I (Hurler syndrome) in the ongoing proof-of-concept clinical trial. As of April 2019, five patients have been enrolled in the trial with follow-up of up to six months. Preliminary data indicate treatment with gene therapy and the selected conditioning regime was well-tolerated in these patients. Engraftment and high IDUA expression were seen in the first two patients with sufficient follow-up to assess these parameters. The trial is expected to enroll up to eight patients by the first half of 2020, with preliminary findings to be reported after one year of follow-up.

For more information please contact: medinfo@orchard-tx.com

Selected MPS I bibliography

 

Mucopolysaccharidosis type IIIA (MPS-IIIA)

Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome type A) is a rare, life-threatening inherited metabolic disease. MPS-IIIA is the most frequent and severe form of Sanfilippo syndrome. MPS-IIIA is caused by a genetic defect in the SGSH (sulfoglycosamine-sulfohydrolase) gene, which results in a deficiency of SGSH, a crucial enzyme involved in the breakdown of glycosaminoglycans.

As a result, glycosaminoglycans accumulate in cells, tissues, and organs, particularly in the brain. Following 1-2 years of normal development after birth, patients will experience a progressive decline in their neurological function, including speech delay and subsequent loss of language, disturbed sleep, hyperactivity, behavioural disturbance, and impulsivity, as well as difficulty with social interactions. As the disease progresses, patients will display signs of withdrawal. In its most severe form, the disease progresses to severe dementia. The behavioural symptoms generally wane with the onset of severe dementia and the decline of motor function. Life expectancy in MPS-III patients is 10-25 years (source: Lavery 2017). The incidence of MPS-IIIA is currently estimated at approximately 1 in 100,000 live births (source: Valstar 2008).

Currently, treatment options for MPS-IIIA are limited to palliative care only. Allogeneic hematopoietic stem cell transplantation has not been shown to correct or relieve the neurological manifestations of the disease to date.

OTL-201: ex vivo autologous lentiviral gene therapy in preclinical development for MPS-IIIA

Orchard is developing OTL-201, ex vivo autologous lentiviral gene therapy for MPS-IIIA. Data from preclinical studies indicate that treatment with OTL-201 was associated with an increase in SGSH enzyme levels in the brain and in normal behaviour in an open field test (source: Sergijenko 2013). Orchard Therapeutics is currently working with its manufacturing partners and with clinical centres specialized in the treatment of metabolic disorders to initiate clinical studies with OTL-201.

Selected MPS IIIA bibliography

 

Mucopolysaccharidosis type IIIB (MPS-IIIB)

Mucopolysaccharidosis type IIIB (MPS-IIIB or Sanfilippo syndrome type B) is a rare, life-threatening inherited metabolic disease that is very similar to MPS-IIIA. MPS-IIIB is caused by a genetic defect in the NAGLU (N-alpha-acetylglucosaminidase) gene, which results in a deficiency of NAGLU, a crucial enzyme involved in the breakdown of glycosaminoglycans. As a result, glycosaminoglycans accumulate in cells, tissues, and organs, particularly in the brain.

Following 1-2 years of normal development after birth, patients will experience a progressive decline in their neurological function, including speech delay and subsequent loss of language, disturbed sleep, hyperactivity, behavioural disturbance, and impulsivity, as well as difficulty with social interactions. As the disease progresses, patients will display signs of withdrawal. In its most severe form, the disease progresses to severe dementia. The behavioural symptoms generally wane with the onset of severe dementia and the decline of motor function. Life expectancy in MPS-III patients is 15-30 years (source: Lavery 2017). The overall incidence of MPS-III is currently estimated at approximately 1.5 in 100,000 live births (source: Valstar 2008), and MPS-IIIB represents about one-third of the overall MPS-III population.

Currently, treatment options are limited to palliative care only. Allogeneic hematopoietic stem cell transplantation has not been shown to correct or relieve the neurological manifestations of the disease to date.

OTL-202: ex vivo autologous lentiviral gene therapy in preclinical development for MPS-IIIB

Orchard is developing OTL-202, ex vivo autologous lentiviral gene therapy for MPS-IIIB. Data from preclinical studies indicate that treatment with OTL-202 is associated with an increase in NAGLU enzyme levels in the brain and in normal behaviour in an open field test (source: Holley 2017). Orchard Therapeutics is currently working with its manufacturing partners and with clinical centres specialized in the treatment of metabolic disorders to initiate clinical studies with OTL-202.

Selected MPS IIIB bibliography