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. Author manuscript; available in PMC: 2015 Sep 17.
Published in final edited form as: Biochim Biophys Acta. 2013 Jun 6;1832(11):1906–1909. doi: 10.1016/j.bbadis.2013.05.026

Pathogenesis and Therapies for Infantile Neuronal Ceroid Lipofuscinosis (infantile CLN1 disease)

Jacqueline A Hawkins-Salsbury 1, Jonathan D Cooper 3,4, Mark S Sands 1,2
PMCID: PMC4573397  NIHMSID: NIHMS500477  PMID: 23747979

Abstract

The Neuronal Ceroid Lipofuscinoses (NCL, Batten Disease) are a group of inherited neurodegenerative diseases. Infantile Neuronal Ceroid lipofuscinosis (INCL, Infantile Batten Disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the life span of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as Juvenile Neuronal Ceroid Lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic.

Keywords: Neuronal Ceroid Lipofuscinosis, Batten Disease, Neurodegeneration, Neuroinflammation, Lysosomal Storage Disease, Gene Therapy

Introduction

Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten Disease, or infantile CLN1 disease) is a rapidly progressing lysosomal storage disorder (LSD) caused by defects in the gene coding for palmitoyl protein thioesterase-1 (CLN1) (Vesa, et al. 1995). This soluble lysosomal enzyme is responsible for cleaving long-chain fatty acid residues from cysteine residues on a multitude of protein targets (Lu, et al. 1996; Verkruyse and Hofmann 1996; Lu, et al. 2002). In the absence of PPT1 activity, undegraded substrates accumulate in both CNS and systemic tissues. Infantile CLN1 disease can be distinguished ultrastructurally from other forms of NCL by the accumulation of granular osmiophilic deposits in the CNS and in cultured fibroblasts. A hallmark of the NCLs, including infantile CLN1 disease, is the progressive accumulation of autofluorescent material (lipofuscin), most notably in the nervous system, but which is also found in some other tissues (Peltonen, et al. 2000). Profound neuronal degeneration, cortical thinning, and overall brain atrophy are prominent features of infantile CLN1 disease (Haltia, et al. 1973; Haltia, et al. 1973). The mass of an affected child's brain at autopsy may be only 50% of a comparably aged normal child's.

Children with infantile CLN1 disease generally develop symptoms around 18 months of age, which include visual defects and blindness, motor and cognitive deficits, seizures and ultimately early death (Santavuori, et al. 1973; Wisniewski, et al. 1992). No treatment or cure is currently available for these children.

Two mouse models of infantile CLN1 disease were developed that are completely deficient in PPT1 activity (Gupta, et al. 2001; Jalanko et al. 2005). These animals recapitulate many features of the human disease including progressive neurodegeneration, cortical thinning, brain atrophy, autofluorescent accumulation, retinal dysfunction, spontaneous seizures, motor deficits and shortened lifespan (Gupta, et al. 2001; Bible, et al. 2004; Griffey, et al. 2005). These mice are accurate phenocopies of the human disease and are valuable tools for studying disease pathogenesis and testing treatment strategies.

The development of treatments for infantile CLN1 disease has been greatly accelerated by the availability accurate mouse models. Unfortunately, few single therapies have provided any extension in lifespan, and as described below, any improvements observed using single therapies have been rather modest. However, emerging data from combination therapies for various LSDs, and in infantile CLN1 disease in particular, suggest that this approach offers much promise for treating this intractable disease.

Enzyme Replacement Therapy

Enzyme replacement therapy, or ERT, is a conceptually simple method for treating an enzyme deficiency. Enzyme replacement therapy takes advantage of the fact that lysosomal enzymes can be secreted by cells and taken up by neighboring cells through a receptor-mediated process; either the mannose-6-phosphate or mannose receptor systems (Kornfeld 1992). This process was originally referred to as ‘cross-correction’ (Neufeld and Fratantoni 1970). Recombinant enzyme that is post-translationally glycosylated and contains terminal mannose or mannsose-6-phosphate residues will be endocytosed by cells in vivo following an injection. Enzyme replacement therapy is relatively effective at treating the systemic disease associated with several other lysosomal storage diseases following intravenous injection. This approach had not, until recently, been attempted in infantile CLN1 disease due to its predominantly neurological pathology. Lysosomal enzymes, in general, do not cross the blood brain barrier (BBB) effectively. Although some systemically delivered recombinant human PPT1 (rhPPT1) does appear to cross the BBB in the mouse model of infantile CLN1 disease, this was in very small amounts (Hu, et al. 2012). Nonetheless, intravenous rhPPT1 delivery was tested for tolerability, tissue distribution, and efficacy in Ppt1−/− mice. Levels of PPT1 activity reached near normal levels in the visceral tissues of treated Ppt1−/− mice. As expected, levels of PPT1 activity in the brain remained quite low, although at high doses a small amount of activity was seen at 2hr post injection. Unfortunately, PPT1 activity was undetectable in the brain by 24hr post injection (Lu, et al. 2010). However, systemically ERT might be able to reduce the disease burden in visceral organs and thus have a positive impact on disease course. Indeed, animals receiving weekly intravenous injections of rhPPT1 from birth had some improvements in neuropathology and significant autofluorescent clearance in visceral tissues (Lu, et al. 2010). Importantly, these animals also had a modest, but significant increase in lifespan from 236 to 271 days, and a similar improvement in motor function. Although intravenous delivery of ERT will likely be ineffective as a stand-alone therapy for infantile CLN1 disease, it may be very effective at treating the systemic disease as part of a combination approach including CNS-targeted therapies. Alternatively, chronic delivery of recombinant enzyme to the CNS through an implantable pump or periodic intrathecal injections might provide significant benefit to the CNS. This approach has resulted in improvements in the CNS in animal models and is being tested in children with different lysosomal enzyme deficiencies (Dierenfeld, et al. 2010; Dodge, et al. 2009; Hemsley, et al. 2009; Lonser, et al. 2005; Macauley and Sands 2009; Vuillemenot, et al. 2011).

Bone Marrow Transplantation

Bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT) have each been employed to treat LSDs for decades. The efficacy of this approach varies with respect to the specific lysosomal storage disease, as well as the age when the transplant is initiated. Like ERT, this approach largely relies on the phenomenon of cross-correction (Neufeld and Fratantoni 1970). It is believed that a small number of normal donor cells of hematopoietic origin can migrate into the brain and supply enzyme to a large number of deficient host cells. Unfortunately, both pre-clinical and clinical experience with BMT alone has proven ineffective for infantile CLN1 disease (Deeg, et al. 1990; Lake, et al. 1997; Lonnqvist, et al. 2001; Macauley et al. 2012). In fact, not only is there no increase in life span but there is a deterioration in motor function in PPT1-deficient mice treated with BMT during the neonatal period (Macauley et al. 2012).

Gene Therapy

Intracranial gene therapy was first attempted in Ppt1−/− mice utilizing a first-generation adeno-associated virus (AAV) vector (AAV2) injected in two locations per hemisphere in the forebrain (Griffey, et al. 2004). A reduction in autofluorescent storage material, as well as increase in brain mass and cortical thickness were reported. Further investigation demonstrated that CNS-directed gene therapy is more efficacious when the cerebellum is targeted along with the forebrain (Griffey, et al. 2006). Significantly greater enzyme activity and reductions in autofluorescent accumulation, as well as increased in brain weight were observed with this improved strategy. Importantly, the combination of forebrain and cerebellar injections resulted in improvements in motor function and decreased seizure activity. Unfortunately, there was no significant increase in life span. In a related study, Ppt1−/− mice were injected intravitreally with the same AAV2-PPT1 vector (Griffey, et al. 2005). The infantile CLN1 disease mice receiving eye-directed gene therapy demonstrating marked improvements in both retinal pathology and function. Interestingly, intravitreal injections allowed for anterograde axonal transport of PPT1 activity into the brains of treated mice and decreased neurodegeneration throughout the optic tracts (Griffey, et al. 2005). This approach, perhaps combined with direct intracranial injections could provide more widespread delivery of PPT1 activity to the CNS. This is vital in a disorder such as infantile CLN1 disease in which CNS pathology is widespread.

A recent study in PPT1-deficient mice demonstrated that bone marrow transplantation can synergize with CNS-directed gene transfer to greatly enhance the efficacy of either approach (Macauley, et al. 2012). As mentioned above, clinical experience has demonstrated that the NCLs are refractory to BMT (Deeg, et al. 1990; Lake, et al. 1997; Lonnqvist, et al. 2001). This was confirmed in the mouse model of INCL, since Ppt1−/− mice receiving BMT had identical life spans as untreated animals (median ~35.5 weeks). Treatment with a second-generation AAV vector (AAV2/5) alone resulted in a a median life span of ~54 weeks. This clearly demonstrates the value of increased PPT1 distribution and expression. Interestingly, and quite surprisingly, animals receiving both AAV2/5-mediated, CNS-directed gene therapy and BMT had a median life span of ~74 weeks. This increase in lifespan is coupled with significant improvements in motor function, with combination-treated animals performing nearly normally until ~56 weeks of age. Consistent with the improved life span and behavioral measures, significant improvements in histological markers of disease were also observed. Although the mechanism of synergy between gene therapy and BMT is not currently known, this strategy holds promise for the treatment of this invariably fatal neurodegenerative disease.

Neuronal Stem Cells

The advancements in recent years in stem cell technology has raised the possibility that neuronal stem cell transplantation might be a viable treatment strategy for infantile CLN1 disease. Stem cells isolated from the human central nervous system have been cultured, purified and banked (Uchida, et al. 2000; Tamaki, et al. 2002). These cells were successfully transplanted into the brains of immunodeficient NOD-SCID mice, which will not reject the human cells (Tamaki, et al. 2002). When normal (PPT1-positive) human neuronal stem cells were transplanted into PPT1-deficient mice on the NOD-SCID background, the cells engrafted and migrated widely throughout the brain (Tamaki, et al. 2009). Interestingly, these cells provided sufficient levels of PPT1 activity to decrease autofluorescence, delay loss of host neurons and improve motor function. These pre-clinical data were used to support a phase one neuronal stem cell clinical trial in infantile CLN1 disease and late infantile CLN2 disease children. Although some safety concerns remain, neuronal stem cell therapy may be an appropriate treatment for infantile CLN1 disease and other LSDs.

Small Molecule Drugs

Small molecule drugs that effectively treat LSDs in general have been elusive. Most small molecule drug treatments tend to target downstream effects of disease, and therefore have limited efficacy. However, two small molecule drugs have shown promise in both cell and whole animal models of infantile CLN1 disease and may be useful as stand-alone treatments or, more likely, as adjunct therapies in combination with other approaches.

Resveratrol

Resveratrol, an antioxidant compound derived from the skins of red grapes, has been shown to decrease oxidative stress and apoptotic markers in cultured cells from an infantile CLN1 disease patient (Yoon, et al. 2011). Oxidative and ER stress have been identified in many LSDs, including INCL (Wei, et al. 2008), where it is known to activate the caspase 9 apoptotic pathway (Kim, et al. 2006; Wei, et al. 2008). Furthermore, PPT1 deficiency leads to disruption of energy metabolism (Woloszynek, et al. 2007; Wei, et al. 2011), presumably related to the ER and oxidative stress. In both PPT1-deficient fibroblasts and mice, treatment with resveratrol improved the energy profile and reduced apoptotic markers (Wei, et al. 2011). Furthermore, Ppt1−/− mice treated with resveratrol in their diet had a significant increase in lifespan, from ~34 weeks to ~37 weeks (Wei, et al. 2011). Although this increase is relatively small, it is nonetheless impressive given the fact the resveratrol does not target the primary cause of disease, PPT1-deficiency. Additionally, resveratrol may reduce BBB permeability in INCL through its anti-inflammatory effects (Saha, et al. 2012). The BBB is somewhat ‘leaky’ in infantile CLN1 disease and it has been suggested that this is due the actions of TH17-lymphocytes and their secretion of matrix metaloproteases, which may degrade tight junctions needed to maintain the barrier (Saha, et al. 2012).

Cysteamine

Lysosomotropic drugs that have similar chemical actions to PPT1 have been proposed as a possible treatment for infantile CLN1 disease since they can localize to the lysosome and cleave thioester linkages similar to PPT1 (Zhang, et al. 2001). Phosphocysteamine is a small molecule drug that meets those criteria. Furthermore, phosphocysteamine is capable of crossing the BBB, which is of obvious importance in INCL (Zhang, et al. 2001). Cultured human lymphoblasts from infantile CLN1 disease patients treated with phosphocysteamine had greatly reduced storage material compared to cells treated with vehicle (Zhang, et al. 2001). While in vitro data clearly demonstrate that phosphocysteamine is not as effective at disrupting thioester linkages as PPT1 (Lu and Hofmann 2006), this remains a potentially viable therapeutic approach. The drug may be able to reduce the load of accumulating products enough to delay disease progression, and might be particularly effective when combined with therapies directed at the root cause of disease. Recently, phosphocysteamine was tested in the mouse model of PPT1-deficiency, both alone and in combination with CNS-directed gene therapy using an AAV2/5 vector (Roberts, et al. 2012). These animals tolerated the therapy well, and were analyzed through behavioral tests as well as histological assessments. As described above, CNS-directed gene therapy provided persistent and significant improvements in lifespan, motor function and histological markers of disease. In contrast, phosphocysteamine alone provided a small and transient improvement in motor function. Additionally, animals receiving phosphocysteamine alone did not have any increase in lifespan or improvements in pathology. The addition of phosphocysteamine to CNS-directed gene therapy did not further improve pathology or lifespan, but did provide additional benefit in motor function (Roberts, et al. 2012). This is promising as it indicates that some clinical benefit can be gained through phosphocysteamine therapy, at least in the area of quality of life. Consistent with the pre-clinical data obtained in the murine model of infantile CLN1 disease, the results of a recent clinical trial in children with INCL showed that systemic treatment with phosphocysteamine provided little clinical benefit (Gavin et al. 2013). However, it remains possible that the addition of this treatment to more complex combination therapy approaches (eg. gene therapy + BMT or gene therapy + ERT) may provide even greater benefit.

Other Neuronal Ceroid Lipofuscinoses

Infantile Neuronal Ceroid Lipofuscinosis is one member of the NCL family of neurodegenerative diseases. There are several other forms of NCL caused by a deficiency in a soluble lysosomal enzyme. The most common being Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL, Late Infantile Batten Disease, or late infantile CLN2 disease) which is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Since both late infantile CLN2 disease and infantile CLN1 disease share a common defect (soluble lysosomal enzyme deficiency), similar therapeutic strategies might be effective for both. In fact, it has been shown that intracerebroventricular or intrathecal administration of recombinant TPP1 reduces neuroinflammation, decreases the accumulation of autofluorescent material, and improves the clinical course of disease in the murine model of late infantile CLN2 disease (Chang et al. 2008; Xu et al. 2011). Encouragingly, intrathecal administration of recombinant TPP1 also reduces lysosomal storage in a large animal model (canine) of late infantile CLN2 disease (Vuillemenot et al. 2011). Interestingly, intravenous administration of recombinant TPP1 also results in ~10% normal levels of enzyme in the CNS (Meng et al 2012). Central nervous system-directed gene therapy using AAV vectors expressing TPP1 has also shown promise in the late infantile CLN2 disease mouse (Passini et al. 2006; Cabrera-Salazar et al. 2007). These pre-clinical experiments led to a clinical trial using an AAV2 vector in children with late infantile CLN2 disease (Worgall et al. 2008). Although there was little benefit observed in the treated children, this approach was well tolerated. It should be noted that this was designed as a safety trial performed in severely affected children. The use of improved AAV vectors in early stage or pre-symptomatic children might provide some clinical benefit. Although these data are promising single treatments have led to only partial correction of late infantile CLN2 disease, similar to the results in infantile CLN1 disease. It would be interesting to determine the efficacy of combination treatments in late infantile CLN2 disease.

A number of NCLs are caused by deficiencies in integral membrane proteins that are not secreted and, therefore, cannot correct surrounding cells in a manner similar to the soluble lysosomal enzymes. Juvenile Neuronal Ceroid Lipofuscinosis (JNCL, Juvenile Batten Disease, or juvenile CLN3 disease) is the most common form of NCL and is caused by a deficiency of an integral membrane protein of unknown function. Since the protein cannot “cross-correct” adjacent cells and the function is unknown, it has been extremely difficult to devise or even envision an effective therapeutic strategy. However, it might be possible to target secondary pathogenic mechanisms and decrease the severity of the disease. It has been shown that the mouse model of juvenile CLN3 disease and children with the disease develop autoantibodies to several proteins, including glutamic acid decarboxylase (GAD65) (Chattopadhyay et al. 2002). It has also been shown that immunosuppression with mycophenolate decreases the neuroinflammation and improves motor function in the mouse model of juvenile CLN3 disease (Seehafer et al. 2011). A clinical trial in JNCL children using mycophenolate has been initiated. However, much more research will be required to determine the function of the protein deficient in juvenile CLN3 disease and develop effective therapies for this invariably fatal disorder.

Conclusions

Infantile CLN1 disease has, until recently, been refractory to most therapeutic interventions. This is likely due to the fact that the CNS is difficult to effectively target. However, it is also possible that providing therapy exclusively to the CNS could limit efficacy. It is known that PPT1 is expressed in virtually every cell type and there is histologic evidence of disease in multiple organ systems, including the heart (Galvin, et al. 2008). With the more recent development of an appropriate mouse model and better understanding of the root causes of disease, advancements in treatment options have been progressing steadily. Although single therapies have generally resulted in modest improvements, the dramatic synergy observed through combining CNS-directed gene therapy and BMT suggests that combinatorial approaches may be the best strategy for treating INCL. Since infantile CLN1 disease has an early onset (6mo-1yr) and rapid progression (death typically by 3-6yr of age), early diagnosis, perhaps through a newborn screening program, will greatly enhance the efficacy of any therapeutic intervention. Other forms of NCL caused by deficiencies in soluble lysosomal will likely respond to similar approaches as those being developed for infantile CLN1 disease. Unfortunately, NCLs caused by deficiencies in integral membrane proteins will require much more research in order to understand the function of the various proteins and to devise effective therapeutic strategies.

Research Highlights.

INCL may theoretically be treated by supplying the missing PPT1 enzyme

Enzyme replacement, gene transfer or stem cell grafts are individually ineffective

Combination therapies have pronounced synergistic effects upon disease progression and lifespan

Footnotes

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Classification:

Neurodegenerative Diseases: Experimental therapies

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