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What is the primary focus of the research published on 08 August 2023?
What is the primary focus of the research published on 08 August 2023?
Which gene is associated with CLN5 Batten disease?
Which gene is associated with CLN5 Batten disease?
What are some characteristics of CLN5 Batten disease?
What are some characteristics of CLN5 Batten disease?
What does the term 'intracerebroventricular' refer to in the context of the study?
What does the term 'intracerebroventricular' refer to in the context of the study?
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Which of the following statements best describes the research findings related to animal testing?
Which of the following statements best describes the research findings related to animal testing?
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What is the significance of dose escalation in this research?
What is the significance of dose escalation in this research?
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What was the main finding regarding transduced cells in the two animals studied?
What was the main finding regarding transduced cells in the two animals studied?
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What asymmetry was observed in the study?
What asymmetry was observed in the study?
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What was concluded about ICV delivery in the current study?
What was concluded about ICV delivery in the current study?
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How long was the maintenance of retinal structure and function observed post-treatment?
How long was the maintenance of retinal structure and function observed post-treatment?
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What was the outcome regarding the untreated eye of CLN5−/− sheep?
What was the outcome regarding the untreated eye of CLN5−/− sheep?
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What was noted about the immunosuppressive drugs in the study?
What was noted about the immunosuppressive drugs in the study?
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What was the primary outcome of the therapy study for CLN5−/− sheep?
What was the primary outcome of the therapy study for CLN5−/− sheep?
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What route of administration was found to provide the most robust distribution of vector throughout the CNS?
What route of administration was found to provide the most robust distribution of vector throughout the CNS?
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Which of the following routes circumvents the blood-brain and blood-CSF barriers?
Which of the following routes circumvents the blood-brain and blood-CSF barriers?
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What was observed about the treated sheep with the lowest therapeutic efficacy?
What was observed about the treated sheep with the lowest therapeutic efficacy?
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Which symptom was noted in the CLN5−/− sheep long after ICV injection?
Which symptom was noted in the CLN5−/− sheep long after ICV injection?
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What was the limitation noted in the long-term treatment efficacy for CLN5−/− sheep?
What was the limitation noted in the long-term treatment efficacy for CLN5−/− sheep?
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What characterized sheep 1164–15 at her untimely death?
What characterized sheep 1164–15 at her untimely death?
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Which finding was NOT associated with systemic (intravenous) delivery of AAV9 vectors?
Which finding was NOT associated with systemic (intravenous) delivery of AAV9 vectors?
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What was the outcome for the untreated CLN5−/− sheep regarding thalamic gliosis and lysosomal storage accumulation?
What was the outcome for the untreated CLN5−/− sheep regarding thalamic gliosis and lysosomal storage accumulation?
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What was a significant observation in the sheep treated with the highest ICV dose?
What was a significant observation in the sheep treated with the highest ICV dose?
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What was the average intracranial volume loss for untreated CLN5−/− sheep?
What was the average intracranial volume loss for untreated CLN5−/− sheep?
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What was the age of the sheep that responded favorably to treatment before clinical decline?
What was the age of the sheep that responded favorably to treatment before clinical decline?
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What was the initial outcome for the advanced symptomatic sheep who were treated?
What was the initial outcome for the advanced symptomatic sheep who were treated?
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Which delivery method showed therapeutic benefit in a canine model of CLN2 NCL?
Which delivery method showed therapeutic benefit in a canine model of CLN2 NCL?
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What impact did the unilateral injection have on the efficacy of treatment in one particular case?
What impact did the unilateral injection have on the efficacy of treatment in one particular case?
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How long did the sheep treated with the highest dose survive after the treatment started?
How long did the sheep treated with the highest dose survive after the treatment started?
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What indicated that the second advanced symptomatic sheep was a non-responder to treatment?
What indicated that the second advanced symptomatic sheep was a non-responder to treatment?
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What was the main clinical issue faced by the treated sheep that ultimately led to euthanasia?
What was the main clinical issue faced by the treated sheep that ultimately led to euthanasia?
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Neuronal ceroid lipofuscinoses (NCLs) are characterized by progressive neurodegeneration and cortical atrophy.
Neuronal ceroid lipofuscinoses (NCLs) are characterized by progressive neurodegeneration and cortical atrophy.
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The CLN5 gene is associated with a dominant pattern of inheritance in Batten disease.
The CLN5 gene is associated with a dominant pattern of inheritance in Batten disease.
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CLN5 disease typically presents with visual decline and seizures starting in infancy.
CLN5 disease typically presents with visual decline and seizures starting in infancy.
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A naturally occurring sheep model of CLN5 NCL exists in New Zealand Borderdale sheep.
A naturally occurring sheep model of CLN5 NCL exists in New Zealand Borderdale sheep.
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The average lifespan of CLN5−/− sheep affected by the disease is typically between 10–20 years.
The average lifespan of CLN5−/− sheep affected by the disease is typically between 10–20 years.
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Healthy CLN5 heterozygous Borderdale sheep are unaffected carriers of the disease.
Healthy CLN5 heterozygous Borderdale sheep are unaffected carriers of the disease.
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Autosomal-recessive mutations in the CLN5 gene lead to impaired cognition and motor dysfunction in affected individuals.
Autosomal-recessive mutations in the CLN5 gene lead to impaired cognition and motor dysfunction in affected individuals.
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ICV administration of scAAV9/oCLN5 was performed on untreated CLN5−/− sheep to analyze treatment efficacy.
ICV administration of scAAV9/oCLN5 was performed on untreated CLN5−/− sheep to analyze treatment efficacy.
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Both single-stranded AAV9 and lentiviral vectors have shown to support the US Food and Drug Administration clearance of the CLN5 gene therapy product.
Both single-stranded AAV9 and lentiviral vectors have shown to support the US Food and Drug Administration clearance of the CLN5 gene therapy product.
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Moderate dose ICV scAAV9/oCLN5 therapy was administered to CLN5−/− sheep at 3 months of age.
Moderate dose ICV scAAV9/oCLN5 therapy was administered to CLN5−/− sheep at 3 months of age.
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Gene therapy administered at earlier stages of disease in patients with neuropathic lysosomal storage diseases may delay disease progression.
Gene therapy administered at earlier stages of disease in patients with neuropathic lysosomal storage diseases may delay disease progression.
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All nine CLN5−/− sheep received the same dosage of ICV scAAV9/oCLN5 therapy regardless of age.
All nine CLN5−/− sheep received the same dosage of ICV scAAV9/oCLN5 therapy regardless of age.
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The study demonstrated significant neurodegeneration in CLN5−/− sheep treated with the highest dose of therapy.
The study demonstrated significant neurodegeneration in CLN5−/− sheep treated with the highest dose of therapy.
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The results suggested that delivery of gene therapy in twelve-month-old CLN5−/− sheep was more effective than at three months old.
The results suggested that delivery of gene therapy in twelve-month-old CLN5−/− sheep was more effective than at three months old.
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Seven sheep experienced a clinically significant slowing of disease progression after receiving high-dose ICV therapy.
Seven sheep experienced a clinically significant slowing of disease progression after receiving high-dose ICV therapy.
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Clinical trials for various forms of NCL have been either completed, ongoing, or in preparation.
Clinical trials for various forms of NCL have been either completed, ongoing, or in preparation.
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The lifespan of CLN5−/− sheep was extended to more than double the natural expectancy due to the therapy.
The lifespan of CLN5−/− sheep was extended to more than double the natural expectancy due to the therapy.
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Sheep receiving intracranial volumes at injection exhibited greater losses compared to untreated CLN5−/− sheep.
Sheep receiving intracranial volumes at injection exhibited greater losses compared to untreated CLN5−/− sheep.
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Administration routes for CLN2 therapeutics include only spinal intrathecal therapy.
Administration routes for CLN2 therapeutics include only spinal intrathecal therapy.
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The treated sheep exhibited severe symptoms like manifest ataxia and seizure activity after treatment.
The treated sheep exhibited severe symptoms like manifest ataxia and seizure activity after treatment.
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The ICV route is increasingly recognized for its ability to transduce widespread areas of the brain in CNS disorders.
The ICV route is increasingly recognized for its ability to transduce widespread areas of the brain in CNS disorders.
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Sheep treated with the least therapeutic efficacy had the highest number of transduced cells.
Sheep treated with the least therapeutic efficacy had the highest number of transduced cells.
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Loss of vision was the only significant symptom observed in the treated CLN5−/− sheep over the study duration.
Loss of vision was the only significant symptom observed in the treated CLN5−/− sheep over the study duration.
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The study concluded that intracisternal delivery was the most effective method for vector distribution throughout the CNS.
The study concluded that intracisternal delivery was the most effective method for vector distribution throughout the CNS.
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Treated sheep who received a high ICV dose exhibited more thalamic gliosis than untreated sheep.
Treated sheep who received a high ICV dose exhibited more thalamic gliosis than untreated sheep.
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One treated sheep began to decline clinically at 19 months post-treatment.
One treated sheep began to decline clinically at 19 months post-treatment.
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All advanced symptomatic sheep responded favorably to treatment.
All advanced symptomatic sheep responded favorably to treatment.
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Bilateral injections have shown therapeutic benefits in multiple animal studies.
Bilateral injections have shown therapeutic benefits in multiple animal studies.
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Untreated CLN5−/− sheep lost an average intracranial volume of 5.4 mL between 3 and 19 months of age.
Untreated CLN5−/− sheep lost an average intracranial volume of 5.4 mL between 3 and 19 months of age.
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One sheep that received treatment experienced minimal intracranial volume loss.
One sheep that received treatment experienced minimal intracranial volume loss.
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The clinical health of the third treated sheep was considered poor prior to euthanasia.
The clinical health of the third treated sheep was considered poor prior to euthanasia.
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Inducible tremors and stereotypical circling behavior were noted in the sheep that finally declined.
Inducible tremors and stereotypical circling behavior were noted in the sheep that finally declined.
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Treatment with ICV scAAV9/oCLN5 resulted in no cognitive decline in sheep.
Treatment with ICV scAAV9/oCLN5 resulted in no cognitive decline in sheep.
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The untreated CLN5−/− sheep exhibited extensive cortical neuroinflammation.
The untreated CLN5−/− sheep exhibited extensive cortical neuroinflammation.
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The average intracranial volume loss for untreated CLN5−/− sheep was approximately 9.4 mL.
The average intracranial volume loss for untreated CLN5−/− sheep was approximately 9.4 mL.
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Mild clinical disease was associated with a rate of decline of -0.5 in the study.
Mild clinical disease was associated with a rate of decline of -0.5 in the study.
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The treatment involving a moderate dose of ICV scAAV9/oCLN5 had an intracranial volume loss of 6.7 grams.
The treatment involving a moderate dose of ICV scAAV9/oCLN5 had an intracranial volume loss of 6.7 grams.
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The rate of change in vision was -1.6 in one of the advanced symptomatic sheep.
The rate of change in vision was -1.6 in one of the advanced symptomatic sheep.
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All treatment groups displayed low cognitive decline rates after administration of scAAV9/oCLN5.
All treatment groups displayed low cognitive decline rates after administration of scAAV9/oCLN5.
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The Control group treated with Nil had a 100% loss of vision.
The Control group treated with Nil had a 100% loss of vision.
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Sheep treated with high doses exhibited extensive cortical thickness reduction.
Sheep treated with high doses exhibited extensive cortical thickness reduction.
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Subcortical structures showed very high neuroinflammation in all treated animals.
Subcortical structures showed very high neuroinflammation in all treated animals.
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Cognitive functions were entirely preserved in all CLN5+/- control sheep.
Cognitive functions were entirely preserved in all CLN5+/- control sheep.
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The study used a total of three different treatment doses to evaluate therapeutic efficacy.
The study used a total of three different treatment doses to evaluate therapeutic efficacy.
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The weight loss for advanced symptomatic sheep was documented as -7.8 grams.
The weight loss for advanced symptomatic sheep was documented as -7.8 grams.
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A high dose of ICV scAAV9/oCLN5 led to low neuroinflammation in the cortex.
A high dose of ICV scAAV9/oCLN5 led to low neuroinflammation in the cortex.
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Treatment efficacy in the study was completely uniform across all tested sheep.
Treatment efficacy in the study was completely uniform across all tested sheep.
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AAV9 gene therapy has only been tested in human models for Niemann-Pick type C1 disease.
AAV9 gene therapy has only been tested in human models for Niemann-Pick type C1 disease.
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CLN5 Batten disease is characterized by neuronal ceroid lipofuscinoses.
CLN5 Batten disease is characterized by neuronal ceroid lipofuscinoses.
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The intracerebroventricular route of administration guarantees complete therapeutic distribution in the CNS.
The intracerebroventricular route of administration guarantees complete therapeutic distribution in the CNS.
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The efficacy of dual intracerebroventricular and intravitreal gene therapy has prompted clinical trials for CLN5 Batten disease.
The efficacy of dual intracerebroventricular and intravitreal gene therapy has prompted clinical trials for CLN5 Batten disease.
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Intravitreal gene therapy prevents retinal dysfunction in sheep models of CLN5 Batten disease.
Intravitreal gene therapy prevents retinal dysfunction in sheep models of CLN5 Batten disease.
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The guidelines for CLN2 disease patients are irrelevant to the treatment of CLN5 Batten disease.
The guidelines for CLN2 disease patients are irrelevant to the treatment of CLN5 Batten disease.
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Electroretinography is a method used in the assessment of CLN2 disease.
Electroretinography is a method used in the assessment of CLN2 disease.
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Cerebrospinal fluid routes are considered for delivering biologics in translational approaches.
Cerebrospinal fluid routes are considered for delivering biologics in translational approaches.
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Study Notes
CLN5 Batten Disease
- CLN5 Batten disease is a rare, inherited, fatal neurodegenerative disorder caused by mutations in the CLN5 gene.
- The disease is characterized by progressive neuronal loss, blindness, and premature death.
- The therapeutic study, based on the findings from CLN5−/− sheep with CLN5 gene therapy, is registered on Clinicaltrials.gov under the identifier NCT05228145.
- The study highlights that the intracerebroventricular (ICV) route of administration resulted in the most robust distribution of the vector throughout the entire central nervous system (CNS) compared to other routes.
- The ICV route was favored for CLN5 therapeutics due to its ability to transduce the CNS widely, circumventing the blood-brain and blood-CSF barriers, minimizing the risk of immune response or off-target side effects.
- The study's findings suggest that higher ICV doses could potentially attenuate subcortical pathology, reducing thalamic gliosis and lysosomal storage accumulation in the thalamus and cerebellum.
- The research demonstrates that unilateral ICV delivery could achieve widespread CNS transduction.
- While the ICV delivery alone was not sufficient to prevent vision loss, combined with an intravitreal (IVT) delivery of scAAV9/oCLN5, retinal structure and function were maintained for up to 15 months in the treated eye of CLN5−/− sheep.
- The study indicated no significant upregulation in neuroinflammation in treated sheep, suggesting long-term transgene expression with no signs of toxicity.
- The study did not provide data on the need for immunomodulation in human CLN5 patients as sheep did not receive immunosuppressive drugs.
- The ovine and human CLN5 transgenes used in the study were codon-optimized, indicating a potential for further study in human CLN5 patients.
- The findings indicate that early treatment is crucial for CLN5 NCL, as the earlier the treatment, the better the outcome.
- The study suggests that higher doses and the inclusion of an ocular delivery route for retinal targeting could be beneficial for treating CLN5 Batten disease.
Therapeutic Potential
- The study demonstrates great promise for extending and improving the quality of life for post-symptomatic CLN5 patients, contingent on sufficient remaining cortical and cerebellar neurons.
- The research supports further exploration of higher doses and the inclusion of an ocular delivery route for retinal targeting in future studies.
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Description
Explore the rare, inherited CLN5 Batten disease, a neurodegenerative disorder marked by severe neurological decline and blindness. This quiz covers the disease's genetic basis, therapeutic studies involving gene therapy, and innovative delivery methods for treatments. Test your knowledge on this important health topic.
