- Email: [email protected]
Development of new treatments for Batten disease
Comment
tozadenant treatment at high doses deserves close attention in future studies. Although Hauser and colleagues’ study9 is a phase 2 trial in which several different doses were tested and compared with placebo, the total number of patients enrolled in this study is fairly large, and the results seem to show an efficacy of this drug similar to that reported in studies of istradefylline and preladenant (table).5–7 The reduction in off-time by 1·1 h with tozadenant 120 and 180 mg twice-daily dose groups combined is also similar to the reported effects of the MAO-B inhibitor rasagiline and the COMT inhibitor entacapone.10 Drug regulators generally regard a reduction in off-time of 1 h as clinically meaningful, which was achieved in 42 (65%) of 65 patients in the 120 mg twice-daily group and 46 (72%) of 64 in the 180 mg twice-daily group in Hauser and colleagues’ study.9 However, all three drug classes (MAO-B inhibitors, COMT inhibitors, and A2A antagonists) could potentially be used together in the same patients to maximize motor control. Overall, this trial provides another strong signal for the potential of A2A antagonists in the management of patients with advanced Parkinson’s disease, and tozadenant should now be assessed in phase 3 trials. *Angelo Antonini, Werner Poewe
AA has received personal fees and non-financial support from UCB and AbbVie, and personal fees from Novartis and GlaxoSmithKline. WP has received personal (lecture and consultancy) fees from AbbVie, AstraZeneca, Teva, Novartis, GlaxoSmithKline, Boehringer Ingelheim, UCB, Orion Pharma, Merck Serono, and Merz Pharma in relation to clinical drug development programmes for Parkinson’s disease. 1 2
3
4
5
6
7
8
9
10
Poewe WH, Lees AJ, Stern GM. Low-dose L-dopa therapy in Parkinson’s disease: a 6-year follow-up study. Neurology 1986; 36: 1528–30. Antonini A, Isaias IU, Rodolfi G,et al. A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. J Neurol 2011; 258: 579–85. Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of Parkinson’s disease: review of recent trials. Mov Disord 2013; 28: 131–44. Bibbiani F, Oh JD, Petzer JP, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol 2003; 184: 285–94. Mizuno Y, Kondo T, Japanese Istradefylline Study Group. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord 2013; 28: 1138–41. Pourcher E, Fernandez HH, Stacy M, Mori A, Ballerini R, Chaikin P. Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord 2012; 18: 178–84. Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 2011; 10: 221–29. Merck. Merck provides update on phase III clinical program for preladenant, the company’s investigational Parkinson’s disease medicine. May 23, 2013. http://www.businesswire.com/news/home/20130523006358/en/MerckUpdate-Phase-III-Clinical-Program-Preladenant (accessed June 20, 2014). Hauser RA, Olanow CW, Kieburtz KD, et al. Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol 2014; published online July 7. http://dx.doi.org/10.1016/S1474-4422(14)70148-6. Rascol O, Brooks DJ, Melamed E, et al, for the LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365: 947–54.
Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo, Venice 30126, Italy (AA); and Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (WP) [email protected]
Development of new treatments for Batten disease The neuronal ceroid lipofuscinoses (also known as Batten disease) are a group of devastating inherited paediatric neurodegenerative diseases for which no curative treatment is available.1 Substantial challenges exist regarding basic biology (since the function of many of the genes associated with this diseases is not known) and therapeutic development. However, the first clinical trials of different treatment approaches are now beginning to yield results (table). The pilot study2 reported by Anil Mukherjee and colleagues in The Lancet Neurology was started more than a decade ago. It assesses whether a combination of cysteamine bitartrate (cystagon) and N-acetylcysteine www.thelancet.com/neurology Vol 13 August 2014
is beneficial to children with one type of neuronal ceroid lipofuscinosis, infantile CLN1 disease. Most neuronal ceroid lipofuscinoses are autosomal recessive disorders, and can be divided into those caused by mutations in genes encoding lysosomal enzymes and those caused by mutations in genes that encode transmembrane proteins, many of which sit in the lysosomal perimeter membrane.5 The diseases are characterised by the storage of autofluorescent material (similar to lipofuscin and ceroid) that accumulates in lysosomes. The components and ultrastructure of the storage vary across the different types of neuronal ceroid lipofuscinosis. In the
Published Online July 3, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70151-6 See Articles page 777
749
Comment
particular type of neuronal ceroid lipofuscinosis being studied by Mukherjee and colleagues2—infantile neuronal ceroid lipofuscinosis—the abnormal storage appears as a granular osmiophilic deposits (GRODs) in electron microscopy of blood lymphocytes or skin biopsy. GRODs are found in most cell types (although the CNS is affected the most) and are associated with cell death. However, no evidence shows that this storage instigates cell death. Most cases of infantile neuronal ceroid lipofuscinosis are caused by mutations in the disease gene PPT1 (also known as CLN1) that encodes a lysosomal palmitoyl thioesterase, an enzyme that cleaves the thioester linking palmitate to palmitoylated proteins destined for degradation. The typical course of CLN1 disease begins in infancy (at 6–12 months), with widespread brain atrophy leading to loss of all cognitive and active motor skills before 3 years of age, and death by 9–13 years of age.6 Milder mutations can cause disease of later onset, such as juvenile and adult CLN1 diseases.7 An ideal treatment for the neuronal ceroid lipofuscinoses would be drug based, because this is a less invasive approach than gene or enzyme replacement, which might require surgical access into
the brain. Treatment with most drugs or with gene or enzyme replacement therapies all face the challenge of crossing the blood–brain barrier. Mukherjee and colleagues2 tested two drugs that were chosen as an alternative way to attack the thioester linkage in the absence of functional PPT1, with the aim of preventing the build-up of ceroid and keeping cells in a healthier state. Both drugs have been reported to exert this action, in addition to having antioxidant properties, and both already in clinical use. Cysteamine bitartrate, which can cross the blood–brain barrier readily, is effective in the treatment of nephropathic cystinosis—a disorder of cystine excretion—and has been used for radiation sickness. N-acetylcysteine is used to treat paracetamol overdose, is inhaled as mucolytic therapy for respiratory problems, and has been used in a range of psychiatric disorders. Its ability to cross the blood–brain barrier remains controversial, although N-acetylcysteine ethyl ester is able to cross the blood–brain barrier. This study2 is a thorough evaluation of the use of these two drugs in combination in nine children who were between 6 months and 3 years of age at enrolment and is beneficial in several ways. It provides additional
Study title
Treatment
Study period and status
Sponsor
Country in which treatment is given
ClinicalTrials.gov identifier
CLN1
Cystagon to treat infantile neuronal ceroid lipofuscinosis (a combination therapy with cystagon and N-acetylcysteine for INCL patients)2
Combination of cysteamine bitartrate and N-acetylcysteine
2001–13; completed
National Institute of Child Health and Human Development (MD, USA)
USA
NCT00028262
CLN1
Safety and efficacy study of human central nervous system stem cells (HuCNS-SC) in subjects with neuronal ceroid lipofuscinosis
Stem cells
2010–11; withdrawn before enrolment
StemCells, Inc (CA, USA)
USA
NCT01238315
CLN1 and CLN2
Study of human central nervous system stem cells (HuCNS- Stem cells SC) in patients with infantile or late infantile neuronal ceroid lipofuscinosis (NCL)3
2006–09; completed
StemCells, Inc
USA
NCT00337636
CLN2
Safety study of a gene transfer vector for children with late infantile neuronal ceroid lipofuscinosis4
AAV2CUhCLN2
2005–19; active, not recruiting
Weill Cornell Medical College (NY, USA)
USA
NCT00151216
CLN2
Safety study of a gene transfer vector (rh.10) for children with late infantile neuronal ceroid lipofuscinosis
AAVrh.10CUhCLN2
2010–16; recruiting
Weill Cornell Medical College
USA
NCT01161576
CLN2
AAVrh.10 administered to children with late infantile neuronal ceroid lipofuscinosis with uncommon genotypes or moderate/severe impairment
AAVrh.10CUhCLN2
2010–14; recruiting
Weill Cornell Medical College
USA
NCT01414985
CLN2
Safety and efficacy study of BMN190 for the treatment of CLN2 patients
rhTPP1 BMN190
2013–16; recruiting
Biomarin Pharmaceutical, Inc (CA, USA)
Germany and UK
NCT01907087
CLN3
Cellcept for treatment of juvenile neuronal ceroid lipofuscinosis
Mycophenolate mofetil
2011–15; recruiting
University of Rochester (NY, USA)
USA
NCT01399047
NCL
Human placental-derived stem cell transplantation (HPDSC) Stem cells
2013–19; recruiting
New York Medical College (NY, USA)
USA
NCT01586455
Table: Summary of clinical trials for neuronal ceroid lipofuscinoses
750
www.thelancet.com/neurology Vol 13 August 2014
Comment
valuable information about the natural history of CLN1 disease linked to specific genotypes, which is essential to judge the efficacy of any treatment trial. The results include a remarkable clearance of GRODs in blood cells and the reduction of irritability associated with the disease in seven children. The observation of reduced irritability alone might affect present clinical practice. The disease course also seemed to be slower than without the drugs when compared with older untreated siblings and historical studies, especially in terms of time until isoelectric electroencephalogram, although it was still unrelenting. Therefore, although these drugs might delay disease progression, the disease is certainly not halted. Future studies could consider the identification and use of biomarkers in monitoring of efficacy, to avoid the need for general anaesthesia, and could use a derivative of N-acetylcysteine that crosses the bloodbrain barrier more efficiently. Work in animal models suggests that the most effective treatment is one that is begun pre-symptomatically. This notion should be considered for a future trial, perhaps targeting children and adults whose disease begins later as well as infants who can be diagnosed sufficiently early. A previous, but smaller, study had tested cysteamine bitartrate in four older children (all >8 years of age and three >13 years of age) with juvenile CLN1 disease, all of whom were treated after their symptoms began.8 These children already had substantial disease symptoms and, although GRODs were reportedly reduced in blood cells, no demonstrable improvement or slowing of the disease course occurred. Clearance of storage is therefore not an appropriate clinical endpoint. Alternatively, the administration of these drugs in combination with other potential approaches, such as enzyme replacement therapy, might be beneficial. The ultimate aim of any treatment for Batten disease is a complete cure for all types of the disorder. A welcome first step would be the development of treatment that stops or delays the progression of at least some types of the disease. Treatment needs to reach the brain and the eye, and almost certainly the periphery, since lysosomal storage is widespread. Several therapeutic options are being considered, with a focus on the most prevalent neuronal ceroid lipofuscinoses and those caused by defects in lysosomal enzymes (CLN1, CLN2, and CLN3 diseases). www.thelancet.com/neurology Vol 13 August 2014
These approaches include gene therapy, stem cell therapy, enzyme therapy, immunotherapy, storage material degradation, inhibition of cell death, and drug therapy. A summary of therapeutic approaches can be found on the University College London, UK, NCL Resource website. The table summarises ongoing or recent clinical trials for neuronal ceroid lipofuscinoses. Disease rating scales are being updated in preparation for future clinical trials, incorporating more detailed natural histories for all types of neuronal ceroid lipofuscinoses (eg, as is being done in a collaborative European effort). An international patient registry is also being coordinated by the University Medical Center Hamburg-Eppendorf, Germany. Whereas once there was no treatment below the horizon for Batten disease, several approaches to therapy are now being developed. Many questions still remain, such as how to ensure that the most vulnerable cells in the brain are targeted efficiently and consideration of peripheral effects of the disease. However, in time, these issues will be addressed and families and patients will be able to face a more hopeful future. Sara E Mole MRC Laboratory for Molecular Cell Biology and UCL Institute of Child Health, University College London, London, WC1E 6BT, UK [email protected] SEM is part of DEM-CHILD, a European collaborative effort that is extending the natural history of the neuronal ceroid lipofuscinoses and supporting a patient registry, and involves clinical participation from other countries worldwide, including the USA. SEM also curates NCL Resource, which contains the NCL mutation database. SEM declares no other competing interests. 1 2
3
4
5
6
7 8
The neuronal ceroid lipofusinoses (Batten disease), 2nd edn. Mole SE, Williams RE, Goebel HH, eds. Oxford: Oxford University Press, 2011. Levin WS, Baker EH, Zein WM, et al. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol 2014; published online July 3. http://dx.doi.org/10.1016/S1474-4422(14)70142-5. Selden NR, Al-Uzri A, Huhn SL, et al. Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. J Neurosurg Pediatr 2013; 11: 643–52. Worgall S, Sondhi D, Hackett NR, et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008; 19: 463–74. Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 2012; 33: 42–63. Santavuori P, Vanhanen S-L, Sainio K, et al. Infantile neuronal ceroid lipofuscinosis (INCL): diagnostic criteria. J Inher Metab Dis 1993; 16: 227–29. Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology 2012; 79: 183–91. Gavin M, Wen GY, Messing J, et al. Substrate reduction therapy in four patients with milder CLN1 mutations and juvenile-onset Batten disease using cysteamine bitartrate. JIMD Rep 2013; 11: 87–92.
751
tozadenant treatment at high doses deserves close attention in future studies. Although Hauser and colleagues’ study9 is a phase 2 trial in which several different doses were tested and compared with placebo, the total number of patients enrolled in this study is fairly large, and the results seem to show an efficacy of this drug similar to that reported in studies of istradefylline and preladenant (table).5–7 The reduction in off-time by 1·1 h with tozadenant 120 and 180 mg twice-daily dose groups combined is also similar to the reported effects of the MAO-B inhibitor rasagiline and the COMT inhibitor entacapone.10 Drug regulators generally regard a reduction in off-time of 1 h as clinically meaningful, which was achieved in 42 (65%) of 65 patients in the 120 mg twice-daily group and 46 (72%) of 64 in the 180 mg twice-daily group in Hauser and colleagues’ study.9 However, all three drug classes (MAO-B inhibitors, COMT inhibitors, and A2A antagonists) could potentially be used together in the same patients to maximize motor control. Overall, this trial provides another strong signal for the potential of A2A antagonists in the management of patients with advanced Parkinson’s disease, and tozadenant should now be assessed in phase 3 trials. *Angelo Antonini, Werner Poewe
AA has received personal fees and non-financial support from UCB and AbbVie, and personal fees from Novartis and GlaxoSmithKline. WP has received personal (lecture and consultancy) fees from AbbVie, AstraZeneca, Teva, Novartis, GlaxoSmithKline, Boehringer Ingelheim, UCB, Orion Pharma, Merck Serono, and Merz Pharma in relation to clinical drug development programmes for Parkinson’s disease. 1 2
3
4
5
6
7
8
9
10
Poewe WH, Lees AJ, Stern GM. Low-dose L-dopa therapy in Parkinson’s disease: a 6-year follow-up study. Neurology 1986; 36: 1528–30. Antonini A, Isaias IU, Rodolfi G,et al. A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. J Neurol 2011; 258: 579–85. Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of Parkinson’s disease: review of recent trials. Mov Disord 2013; 28: 131–44. Bibbiani F, Oh JD, Petzer JP, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol 2003; 184: 285–94. Mizuno Y, Kondo T, Japanese Istradefylline Study Group. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord 2013; 28: 1138–41. Pourcher E, Fernandez HH, Stacy M, Mori A, Ballerini R, Chaikin P. Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord 2012; 18: 178–84. Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 2011; 10: 221–29. Merck. Merck provides update on phase III clinical program for preladenant, the company’s investigational Parkinson’s disease medicine. May 23, 2013. http://www.businesswire.com/news/home/20130523006358/en/MerckUpdate-Phase-III-Clinical-Program-Preladenant (accessed June 20, 2014). Hauser RA, Olanow CW, Kieburtz KD, et al. Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol 2014; published online July 7. http://dx.doi.org/10.1016/S1474-4422(14)70148-6. Rascol O, Brooks DJ, Melamed E, et al, for the LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365: 947–54.
Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo, Venice 30126, Italy (AA); and Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (WP) [email protected]
Development of new treatments for Batten disease The neuronal ceroid lipofuscinoses (also known as Batten disease) are a group of devastating inherited paediatric neurodegenerative diseases for which no curative treatment is available.1 Substantial challenges exist regarding basic biology (since the function of many of the genes associated with this diseases is not known) and therapeutic development. However, the first clinical trials of different treatment approaches are now beginning to yield results (table). The pilot study2 reported by Anil Mukherjee and colleagues in The Lancet Neurology was started more than a decade ago. It assesses whether a combination of cysteamine bitartrate (cystagon) and N-acetylcysteine www.thelancet.com/neurology Vol 13 August 2014
is beneficial to children with one type of neuronal ceroid lipofuscinosis, infantile CLN1 disease. Most neuronal ceroid lipofuscinoses are autosomal recessive disorders, and can be divided into those caused by mutations in genes encoding lysosomal enzymes and those caused by mutations in genes that encode transmembrane proteins, many of which sit in the lysosomal perimeter membrane.5 The diseases are characterised by the storage of autofluorescent material (similar to lipofuscin and ceroid) that accumulates in lysosomes. The components and ultrastructure of the storage vary across the different types of neuronal ceroid lipofuscinosis. In the
Published Online July 3, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70151-6 See Articles page 777
749
Comment
particular type of neuronal ceroid lipofuscinosis being studied by Mukherjee and colleagues2—infantile neuronal ceroid lipofuscinosis—the abnormal storage appears as a granular osmiophilic deposits (GRODs) in electron microscopy of blood lymphocytes or skin biopsy. GRODs are found in most cell types (although the CNS is affected the most) and are associated with cell death. However, no evidence shows that this storage instigates cell death. Most cases of infantile neuronal ceroid lipofuscinosis are caused by mutations in the disease gene PPT1 (also known as CLN1) that encodes a lysosomal palmitoyl thioesterase, an enzyme that cleaves the thioester linking palmitate to palmitoylated proteins destined for degradation. The typical course of CLN1 disease begins in infancy (at 6–12 months), with widespread brain atrophy leading to loss of all cognitive and active motor skills before 3 years of age, and death by 9–13 years of age.6 Milder mutations can cause disease of later onset, such as juvenile and adult CLN1 diseases.7 An ideal treatment for the neuronal ceroid lipofuscinoses would be drug based, because this is a less invasive approach than gene or enzyme replacement, which might require surgical access into
the brain. Treatment with most drugs or with gene or enzyme replacement therapies all face the challenge of crossing the blood–brain barrier. Mukherjee and colleagues2 tested two drugs that were chosen as an alternative way to attack the thioester linkage in the absence of functional PPT1, with the aim of preventing the build-up of ceroid and keeping cells in a healthier state. Both drugs have been reported to exert this action, in addition to having antioxidant properties, and both already in clinical use. Cysteamine bitartrate, which can cross the blood–brain barrier readily, is effective in the treatment of nephropathic cystinosis—a disorder of cystine excretion—and has been used for radiation sickness. N-acetylcysteine is used to treat paracetamol overdose, is inhaled as mucolytic therapy for respiratory problems, and has been used in a range of psychiatric disorders. Its ability to cross the blood–brain barrier remains controversial, although N-acetylcysteine ethyl ester is able to cross the blood–brain barrier. This study2 is a thorough evaluation of the use of these two drugs in combination in nine children who were between 6 months and 3 years of age at enrolment and is beneficial in several ways. It provides additional
Study title
Treatment
Study period and status
Sponsor
Country in which treatment is given
ClinicalTrials.gov identifier
CLN1
Cystagon to treat infantile neuronal ceroid lipofuscinosis (a combination therapy with cystagon and N-acetylcysteine for INCL patients)2
Combination of cysteamine bitartrate and N-acetylcysteine
2001–13; completed
National Institute of Child Health and Human Development (MD, USA)
USA
NCT00028262
CLN1
Safety and efficacy study of human central nervous system stem cells (HuCNS-SC) in subjects with neuronal ceroid lipofuscinosis
Stem cells
2010–11; withdrawn before enrolment
StemCells, Inc (CA, USA)
USA
NCT01238315
CLN1 and CLN2
Study of human central nervous system stem cells (HuCNS- Stem cells SC) in patients with infantile or late infantile neuronal ceroid lipofuscinosis (NCL)3
2006–09; completed
StemCells, Inc
USA
NCT00337636
CLN2
Safety study of a gene transfer vector for children with late infantile neuronal ceroid lipofuscinosis4
AAV2CUhCLN2
2005–19; active, not recruiting
Weill Cornell Medical College (NY, USA)
USA
NCT00151216
CLN2
Safety study of a gene transfer vector (rh.10) for children with late infantile neuronal ceroid lipofuscinosis
AAVrh.10CUhCLN2
2010–16; recruiting
Weill Cornell Medical College
USA
NCT01161576
CLN2
AAVrh.10 administered to children with late infantile neuronal ceroid lipofuscinosis with uncommon genotypes or moderate/severe impairment
AAVrh.10CUhCLN2
2010–14; recruiting
Weill Cornell Medical College
USA
NCT01414985
CLN2
Safety and efficacy study of BMN190 for the treatment of CLN2 patients
rhTPP1 BMN190
2013–16; recruiting
Biomarin Pharmaceutical, Inc (CA, USA)
Germany and UK
NCT01907087
CLN3
Cellcept for treatment of juvenile neuronal ceroid lipofuscinosis
Mycophenolate mofetil
2011–15; recruiting
University of Rochester (NY, USA)
USA
NCT01399047
NCL
Human placental-derived stem cell transplantation (HPDSC) Stem cells
2013–19; recruiting
New York Medical College (NY, USA)
USA
NCT01586455
Table: Summary of clinical trials for neuronal ceroid lipofuscinoses
750
www.thelancet.com/neurology Vol 13 August 2014
Comment
valuable information about the natural history of CLN1 disease linked to specific genotypes, which is essential to judge the efficacy of any treatment trial. The results include a remarkable clearance of GRODs in blood cells and the reduction of irritability associated with the disease in seven children. The observation of reduced irritability alone might affect present clinical practice. The disease course also seemed to be slower than without the drugs when compared with older untreated siblings and historical studies, especially in terms of time until isoelectric electroencephalogram, although it was still unrelenting. Therefore, although these drugs might delay disease progression, the disease is certainly not halted. Future studies could consider the identification and use of biomarkers in monitoring of efficacy, to avoid the need for general anaesthesia, and could use a derivative of N-acetylcysteine that crosses the bloodbrain barrier more efficiently. Work in animal models suggests that the most effective treatment is one that is begun pre-symptomatically. This notion should be considered for a future trial, perhaps targeting children and adults whose disease begins later as well as infants who can be diagnosed sufficiently early. A previous, but smaller, study had tested cysteamine bitartrate in four older children (all >8 years of age and three >13 years of age) with juvenile CLN1 disease, all of whom were treated after their symptoms began.8 These children already had substantial disease symptoms and, although GRODs were reportedly reduced in blood cells, no demonstrable improvement or slowing of the disease course occurred. Clearance of storage is therefore not an appropriate clinical endpoint. Alternatively, the administration of these drugs in combination with other potential approaches, such as enzyme replacement therapy, might be beneficial. The ultimate aim of any treatment for Batten disease is a complete cure for all types of the disorder. A welcome first step would be the development of treatment that stops or delays the progression of at least some types of the disease. Treatment needs to reach the brain and the eye, and almost certainly the periphery, since lysosomal storage is widespread. Several therapeutic options are being considered, with a focus on the most prevalent neuronal ceroid lipofuscinoses and those caused by defects in lysosomal enzymes (CLN1, CLN2, and CLN3 diseases). www.thelancet.com/neurology Vol 13 August 2014
These approaches include gene therapy, stem cell therapy, enzyme therapy, immunotherapy, storage material degradation, inhibition of cell death, and drug therapy. A summary of therapeutic approaches can be found on the University College London, UK, NCL Resource website. The table summarises ongoing or recent clinical trials for neuronal ceroid lipofuscinoses. Disease rating scales are being updated in preparation for future clinical trials, incorporating more detailed natural histories for all types of neuronal ceroid lipofuscinoses (eg, as is being done in a collaborative European effort). An international patient registry is also being coordinated by the University Medical Center Hamburg-Eppendorf, Germany. Whereas once there was no treatment below the horizon for Batten disease, several approaches to therapy are now being developed. Many questions still remain, such as how to ensure that the most vulnerable cells in the brain are targeted efficiently and consideration of peripheral effects of the disease. However, in time, these issues will be addressed and families and patients will be able to face a more hopeful future. Sara E Mole MRC Laboratory for Molecular Cell Biology and UCL Institute of Child Health, University College London, London, WC1E 6BT, UK [email protected] SEM is part of DEM-CHILD, a European collaborative effort that is extending the natural history of the neuronal ceroid lipofuscinoses and supporting a patient registry, and involves clinical participation from other countries worldwide, including the USA. SEM also curates NCL Resource, which contains the NCL mutation database. SEM declares no other competing interests. 1 2
3
4
5
6
7 8
The neuronal ceroid lipofusinoses (Batten disease), 2nd edn. Mole SE, Williams RE, Goebel HH, eds. Oxford: Oxford University Press, 2011. Levin WS, Baker EH, Zein WM, et al. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol 2014; published online July 3. http://dx.doi.org/10.1016/S1474-4422(14)70142-5. Selden NR, Al-Uzri A, Huhn SL, et al. Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. J Neurosurg Pediatr 2013; 11: 643–52. Worgall S, Sondhi D, Hackett NR, et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008; 19: 463–74. Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 2012; 33: 42–63. Santavuori P, Vanhanen S-L, Sainio K, et al. Infantile neuronal ceroid lipofuscinosis (INCL): diagnostic criteria. J Inher Metab Dis 1993; 16: 227–29. Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology 2012; 79: 183–91. Gavin M, Wen GY, Messing J, et al. Substrate reduction therapy in four patients with milder CLN1 mutations and juvenile-onset Batten disease using cysteamine bitartrate. JIMD Rep 2013; 11: 87–92.
751