CLN5 Batten Disease Overview
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Questions and Answers

What is the primary focus of the research published on 08 August 2023?

  • Long-term safety and dose escalation of CLN5 gene therapy (correct)
  • The genetic mutations in sheep
  • The effectiveness of gene therapy in human patients
  • Clinical trials of neurodegenerative disorders

Which gene is associated with CLN5 Batten disease?

  • CLN6
  • CLN1
  • CLN5 (correct)
  • CLN3

What are some characteristics of CLN5 Batten disease?

  • Muscle degeneration and immune system enhancement
  • Increased cognitive abilities and late onset
  • Reversible symptoms and long life expectancy
  • Progressive neuronal loss, blindness, and premature death (correct)

What does the term 'intracerebroventricular' refer to in the context of the study?

<p>Gene therapy delivered to the brain's ventricles (D)</p> Signup and view all the answers

Which of the following statements best describes the research findings related to animal testing?

<p>The study provides evidence supporting clinical translation. (D)</p> Signup and view all the answers

What is the significance of dose escalation in this research?

<p>It allows researchers to find the most effective dosage. (C)</p> Signup and view all the answers

What was the main finding regarding transduced cells in the two animals studied?

<p>There were fewer transduced cells in both animals. (D)</p> Signup and view all the answers

What asymmetry was observed in the study?

<p>Increased amount of transduced neurons in the right column. (A)</p> Signup and view all the answers

What was concluded about ICV delivery in the current study?

<p>ICV delivery was ineffective in addressing vision loss. (A)</p> Signup and view all the answers

How long was the maintenance of retinal structure and function observed post-treatment?

<p>15 months (B)</p> Signup and view all the answers

What was the outcome regarding the untreated eye of CLN5−/− sheep?

<p>It showed severe atrophy and decline post-treatment. (D)</p> Signup and view all the answers

What was noted about the immunosuppressive drugs in the study?

<p>The sheep did not receive any immunosuppressive drugs. (D)</p> Signup and view all the answers

What was the primary outcome of the therapy study for CLN5−/− sheep?

<p>Improved quality of life and extended lifespan (C)</p> Signup and view all the answers

What route of administration was found to provide the most robust distribution of vector throughout the CNS?

<p>Intracerebroventricular (ICV) (C)</p> Signup and view all the answers

Which of the following routes circumvents the blood-brain and blood-CSF barriers?

<p>Cerebrospinal fluid (CSF) delivery (D)</p> Signup and view all the answers

What was observed about the treated sheep with the lowest therapeutic efficacy?

<p>It showed the least number of transduced cells. (D)</p> Signup and view all the answers

Which symptom was noted in the CLN5−/− sheep long after ICV injection?

<p>Loss of vision (A)</p> Signup and view all the answers

What was the limitation noted in the long-term treatment efficacy for CLN5−/− sheep?

<p>Efficacy was not complete. (B)</p> Signup and view all the answers

What characterized sheep 1164–15 at her untimely death?

<p>Mild episodes of stereotypical behavior (D)</p> Signup and view all the answers

Which finding was NOT associated with systemic (intravenous) delivery of AAV9 vectors?

<p>Long-term treatment efficacy (A)</p> Signup and view all the answers

What was the outcome for the untreated CLN5−/− sheep regarding thalamic gliosis and lysosomal storage accumulation?

<p>They exhibited more gliosis and higher storage accumulation. (B)</p> Signup and view all the answers

What was a significant observation in the sheep treated with the highest ICV dose?

<p>They had less thalamic gliosis and lysosomal storage accumulation. (D)</p> Signup and view all the answers

What was the average intracranial volume loss for untreated CLN5−/− sheep?

<p>9.4 mL (A)</p> Signup and view all the answers

What was the age of the sheep that responded favorably to treatment before clinical decline?

<p>9 months (C)</p> Signup and view all the answers

What was the initial outcome for the advanced symptomatic sheep who were treated?

<p>There was stabilization of disease progression. (D)</p> Signup and view all the answers

Which delivery method showed therapeutic benefit in a canine model of CLN2 NCL?

<p>Unilateral injection (A)</p> Signup and view all the answers

What impact did the unilateral injection have on the efficacy of treatment in one particular case?

<p>It had no apparent impact on efficacy. (C)</p> Signup and view all the answers

How long did the sheep treated with the highest dose survive after the treatment started?

<p>30.9 months (A)</p> Signup and view all the answers

What indicated that the second advanced symptomatic sheep was a non-responder to treatment?

<p>It remained clinically stable without change. (D)</p> Signup and view all the answers

What was the main clinical issue faced by the treated sheep that ultimately led to euthanasia?

<p>Inducible tremors and stereotypical circling behavior (D)</p> Signup and view all the answers

Neuronal ceroid lipofuscinoses (NCLs) are characterized by progressive neurodegeneration and cortical atrophy.

<p>True (A)</p> Signup and view all the answers

The CLN5 gene is associated with a dominant pattern of inheritance in Batten disease.

<p>False (B)</p> Signup and view all the answers

CLN5 disease typically presents with visual decline and seizures starting in infancy.

<p>False (B)</p> Signup and view all the answers

A naturally occurring sheep model of CLN5 NCL exists in New Zealand Borderdale sheep.

<p>True (A)</p> Signup and view all the answers

The average lifespan of CLN5−/− sheep affected by the disease is typically between 10–20 years.

<p>False (B)</p> Signup and view all the answers

Healthy CLN5 heterozygous Borderdale sheep are unaffected carriers of the disease.

<p>True (A)</p> Signup and view all the answers

Autosomal-recessive mutations in the CLN5 gene lead to impaired cognition and motor dysfunction in affected individuals.

<p>True (A)</p> Signup and view all the answers

ICV administration of scAAV9/oCLN5 was performed on untreated CLN5−/− sheep to analyze treatment efficacy.

<p>False (B)</p> Signup and view all the answers

Both single-stranded AAV9 and lentiviral vectors have shown to support the US Food and Drug Administration clearance of the CLN5 gene therapy product.

<p>True (A)</p> Signup and view all the answers

Moderate dose ICV scAAV9/oCLN5 therapy was administered to CLN5−/− sheep at 3 months of age.

<p>False (B)</p> Signup and view all the answers

Gene therapy administered at earlier stages of disease in patients with neuropathic lysosomal storage diseases may delay disease progression.

<p>True (A)</p> Signup and view all the answers

All nine CLN5−/− sheep received the same dosage of ICV scAAV9/oCLN5 therapy regardless of age.

<p>False (B)</p> Signup and view all the answers

The study demonstrated significant neurodegeneration in CLN5−/− sheep treated with the highest dose of therapy.

<p>False (B)</p> Signup and view all the answers

The results suggested that delivery of gene therapy in twelve-month-old CLN5−/− sheep was more effective than at three months old.

<p>False (B)</p> Signup and view all the answers

Seven sheep experienced a clinically significant slowing of disease progression after receiving high-dose ICV therapy.

<p>True (A)</p> Signup and view all the answers

Clinical trials for various forms of NCL have been either completed, ongoing, or in preparation.

<p>True (A)</p> Signup and view all the answers

The lifespan of CLN5−/− sheep was extended to more than double the natural expectancy due to the therapy.

<p>True (A)</p> Signup and view all the answers

Sheep receiving intracranial volumes at injection exhibited greater losses compared to untreated CLN5−/− sheep.

<p>False (B)</p> Signup and view all the answers

Administration routes for CLN2 therapeutics include only spinal intrathecal therapy.

<p>False (B)</p> Signup and view all the answers

The treated sheep exhibited severe symptoms like manifest ataxia and seizure activity after treatment.

<p>False (B)</p> Signup and view all the answers

The ICV route is increasingly recognized for its ability to transduce widespread areas of the brain in CNS disorders.

<p>True (A)</p> Signup and view all the answers

Sheep treated with the least therapeutic efficacy had the highest number of transduced cells.

<p>False (B)</p> Signup and view all the answers

Loss of vision was the only significant symptom observed in the treated CLN5−/− sheep over the study duration.

<p>True (A)</p> Signup and view all the answers

The study concluded that intracisternal delivery was the most effective method for vector distribution throughout the CNS.

<p>False (B)</p> Signup and view all the answers

Treated sheep who received a high ICV dose exhibited more thalamic gliosis than untreated sheep.

<p>False (B)</p> Signup and view all the answers

One treated sheep began to decline clinically at 19 months post-treatment.

<p>True (A)</p> Signup and view all the answers

All advanced symptomatic sheep responded favorably to treatment.

<p>False (B)</p> Signup and view all the answers

Bilateral injections have shown therapeutic benefits in multiple animal studies.

<p>True (A)</p> Signup and view all the answers

Untreated CLN5−/− sheep lost an average intracranial volume of 5.4 mL between 3 and 19 months of age.

<p>False (B)</p> Signup and view all the answers

One sheep that received treatment experienced minimal intracranial volume loss.

<p>True (A)</p> Signup and view all the answers

The clinical health of the third treated sheep was considered poor prior to euthanasia.

<p>False (B)</p> Signup and view all the answers

Inducible tremors and stereotypical circling behavior were noted in the sheep that finally declined.

<p>True (A)</p> Signup and view all the answers

Treatment with ICV scAAV9/oCLN5 resulted in no cognitive decline in sheep.

<p>False (B)</p> Signup and view all the answers

The untreated CLN5−/− sheep exhibited extensive cortical neuroinflammation.

<p>True (A)</p> Signup and view all the answers

The average intracranial volume loss for untreated CLN5−/− sheep was approximately 9.4 mL.

<p>True (A)</p> Signup and view all the answers

Mild clinical disease was associated with a rate of decline of -0.5 in the study.

<p>False (B)</p> Signup and view all the answers

The treatment involving a moderate dose of ICV scAAV9/oCLN5 had an intracranial volume loss of 6.7 grams.

<p>False (B)</p> Signup and view all the answers

The rate of change in vision was -1.6 in one of the advanced symptomatic sheep.

<p>True (A)</p> Signup and view all the answers

All treatment groups displayed low cognitive decline rates after administration of scAAV9/oCLN5.

<p>False (B)</p> Signup and view all the answers

The Control group treated with Nil had a 100% loss of vision.

<p>False (B)</p> Signup and view all the answers

Sheep treated with high doses exhibited extensive cortical thickness reduction.

<p>True (A)</p> Signup and view all the answers

Subcortical structures showed very high neuroinflammation in all treated animals.

<p>False (B)</p> Signup and view all the answers

Cognitive functions were entirely preserved in all CLN5+/- control sheep.

<p>True (A)</p> Signup and view all the answers

The study used a total of three different treatment doses to evaluate therapeutic efficacy.

<p>True (A)</p> Signup and view all the answers

The weight loss for advanced symptomatic sheep was documented as -7.8 grams.

<p>False (B)</p> Signup and view all the answers

A high dose of ICV scAAV9/oCLN5 led to low neuroinflammation in the cortex.

<p>False (B)</p> Signup and view all the answers

Treatment efficacy in the study was completely uniform across all tested sheep.

<p>False (B)</p> Signup and view all the answers

AAV9 gene therapy has only been tested in human models for Niemann-Pick type C1 disease.

<p>False (B)</p> Signup and view all the answers

CLN5 Batten disease is characterized by neuronal ceroid lipofuscinoses.

<p>True (A)</p> Signup and view all the answers

The intracerebroventricular route of administration guarantees complete therapeutic distribution in the CNS.

<p>False (B)</p> Signup and view all the answers

The efficacy of dual intracerebroventricular and intravitreal gene therapy has prompted clinical trials for CLN5 Batten disease.

<p>True (A)</p> Signup and view all the answers

Intravitreal gene therapy prevents retinal dysfunction in sheep models of CLN5 Batten disease.

<p>True (A)</p> Signup and view all the answers

The guidelines for CLN2 disease patients are irrelevant to the treatment of CLN5 Batten disease.

<p>False (B)</p> Signup and view all the answers

Electroretinography is a method used in the assessment of CLN2 disease.

<p>False (B)</p> Signup and view all the answers

Cerebrospinal fluid routes are considered for delivering biologics in translational approaches.

<p>True (A)</p> Signup and view all the answers

Flashcards

CLN5 Batten Disease

A rare, inherited, fatal neurodegenerative disorder caused by mutations in the CLN5 gene, characterized by progressive neuronal loss, blindness, and premature death.

Mutations in CLN5 gene

Genetic changes in the CLN5 gene that cause CLN5 Batten disease.

Intracerebroventricular (ICV) route

A method of delivering treatment directly into the brain's ventricles.

Central Nervous System (CNS)

The brain and spinal cord.

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Blood-brain barrier

A protective barrier that regulates what substances can enter the brain from the bloodstream.

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Blood-CSF barrier

A barrier that regulates what substances can enter the cerebrospinal fluid from the bloodstream.

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Intravitreal (IVT) delivery

A method of delivering treatment directly into the eye.

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Therapeutic study

A study to test a potential treatment's effectiveness.

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Gene therapy

Treatment that attempts to fix a faulty gene.

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Clinical trials

Research studies that evaluate new treatments in people.

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Clinicaltrials.gov

A website that lists publicly registered clinical trials.

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Ovine CLN5 transgenes

Optimized sheep versions of the CLN5 gene used in the study.

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Codon-optimized

Modified genes designed for better expression in targeted cells.

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Neuroinflammation

Inflammation in the nervous system.

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Immunomodulation

Methods to adjust the immune response.

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Subcortical pathology

Damage to brain regions below the cortex.

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Thalamic gliosis

Abnormal growth of glial cells in the thalamus.

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Lysosomal storage accumulation

An excessive build up of materials in lysosomes of brain cells.

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Early treatment

Treatment started as soon as possible after symptoms develop.

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Therapeutic potential

The possibility of a treatment improving the lives of patients through the use of existing or potential new therapies.

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NCLs (Batten disease)

A group of inherited lysosomal storage diseases causing progressive neurodegeneration, atrophy, and blindness.

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CLN5 gene

A gene linked to a type of Batten disease, encoding a lysosomal protein.

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Borderdale sheep model

Sheep naturally exhibiting a condition mirroring human CLN5 disease.

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Intracerebroventricular (ICV) administration

Direct injection of treatment into the brain's ventricles.

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scAAV9/oCLN5 vector

Virus-based delivery system carrying the sheep CLN5 gene.

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Animal Ethics Committee

Committee reviewing and approving animal research protocols.

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Lysosomal storage diseases

A group of diseases where waste materials build up in lysosomes.

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Autosomal-recessive mutations

Genetic changes needing a copy from both parents to cause disease.

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CLN5 gene therapy

A treatment approach aiming to correct the faulty CLN5 gene to potentially cure Batten disease.

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AAV9 vector

A virus modified to carry therapeutic genes into the central nervous system.

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ICV delivery

Delivering treatment directly into the brain's ventricles.

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CLN5−/− sheep

Sheep genetically modified to have a missing or non-functional CLN5 gene, mimicking Batten disease.

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Disease progression (CLN5)

The worsening of symptoms associated with Batten disease over time.

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Early treatment (Batten disease)

Administering gene therapy to an individual before pronounced symptoms appear.

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Gene therapy clinical trials

Research studies testing gene therapy for treatment in humans.

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Therapeutic vector platforms

Different types of vectors used to deliver therapeutic genes or treatments to target cells or areas.

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ICV scAAV9/oCLN5

A treatment method for CLN5 Batten disease that involves delivering a corrected CLN5 gene directly into the brain's ventricles using a specialized virus.

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Sheep Study

A clinical experiment using sheep to evaluate the efficacy of a treatment for a particular disease or condition.

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Clinical Decline Rate

Measure of disease progression monitored by observing the rate of worsening of symptoms.

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Intracranial Volume Loss

Decrease in the volume of the brain area related to symptoms

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Cortical Thickness

Measurement of the thickness of the outermost layer of the brain (cortex).

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Neuroinflammation

Inflammation in the nervous system.

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Lysosomal Storage

Buildup of unnecessary materials within lysosomes of brain cells.

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CLN5 Expression

The level of CLN5 protein produced and present in brain cells.

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Control Group

A group of participants in a study who do not receive the experimental treatment.

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Untreated CLN5 -/-

A group of people without a treatment or a functional copy of the CLN5 gene.

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ICV

Intracerebroventricular - administering treatments into the brain ventricles.

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High Dose

Increased amount of treatment given in the study.

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Moderate Dose

A medium amount of treatment used in the study.

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Delayed Clinical Disease

Condition where symptoms are postponed.

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High ICV dose effect

Sheep receiving the highest dose of ICV treatment showed less brain damage (gliosis and storage) than untreated ones, suggesting higher doses might improve outcomes.

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ICV Delivery

Treatment delivered directly into the brain's ventricles (fluid-filled spaces).

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Unilateral ICV treatment

Treatment delivered to just one side of the brain, as opposed to both; showed positive outcomes in some models

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CLN5−/− Sheep

Sheep with a genetic mutation preventing the proper function of the CLN5 gene.

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Lifespan Extension

Treatment prolonged the life of CLN5−/− sheep to more than double or triple their normal lifespan.

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9-month treatment response

One sheep treated at 9 months showed stabilized disease progression until 19 months post-treatment, before worsening.

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ICV volume loss comparison

Treated sheep lost less brain volume than untreated ones over time, indicating possible benefit

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Treatment Efficacy

Measure of how well a treatment works, evaluated by lessening disease-related brain damage.

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Intracerebral Volumes

Brain volumes in the treated and untreated CLN5−/− sheep, measured over the study period.

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Non-responder

One treated sheep did not show improvement or benefit from the ICV treatment

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Bilateral ICV delivery

Treatment injected into both sides of the brain, the most common route in such studies

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CNS Transduction

The ability of a treatment to spread widely through the brain and spinal cord.

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Limited vector availability

Restricted access prevented advanced sheep from getting the better treatment

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Blood-Brain Barrier (BBB)

A protective barrier between the brain's tissues and bloodstream.

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Phenotypic Changes

Observable changes in the appearance or behavior of the CLN5−/− sheep.

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Treatment of advanced symptomatic sheep

Treatment given to sheep showing symptoms. Advanced sheep given a reduced treatment options

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Gene therapy efficacy

The success rate of gene therapy in treating a disease.

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CLN5 Batten disease

A rare genetic disorder causing progressive nervous system damage.

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Intravitreal gene therapy

Gene therapy delivered directly into the eye.

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Animal model for treatment

Use of animals to test potential therapies for human conditions.

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ICV administration

Method of delivering treatment directly into brain ventricles.

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Ovine CLN5 transgene

Sheep version of the CLN5 gene used in research.

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Lysosomal storage accumulation

Buildup of waste materials in lysosomes, negatively affecting brain cells.

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Dual ICV/IVT gene therapy

Gene therapy delivered both into the brain and eye.

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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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Gene Therapy Batten Disease Sheep PDF 2023

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.

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