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What is the prognosis?

Without treatment, affected children suffer loss of their sight, mental impairment, worsening seizures, and the progressive loss of their motor skills. Eventually, those with one of 13 forms of Batten disease become bedridden, require 24-hour care, and die prematurely.1 How quickly symptoms develop and the length of the course of disease depends on symptom onset (Table 1).

Classic forms of Batten

Batten form Age of onset End of life
Infantile 6 months to 2 years old Mid-childhood
Late Infantile 2 to 4 years old 8 to 10 years old
Juvenile 5 to 10 years old Late teens to early 20s
Adult 25 to 43 years old Normal lifespan

Table 1

What governs the age of onset?

The juvenile form of Batten disease was named after Frederick Batten, MA, MD, FRCP, when he reported on two sisters with the disease in 1903.2,3 As various forms of Batten were discovered, each was named according to its age of onset (Table 1). This was very simple when there were only four known forms [infantile, late infantile, juvenile and adult]. However, several variant forms were discovered complicating the matter. It wasn’t until the first genes associated with Batten disease were discovered, researchers learned that different genes were commonly implicated in each form of Batten yet these were not exclusive designations as mistakes in the same gene could result in the same disease with various ages of onset. 4,5,6 In other words, mistakes in the CLN1 gene can cause disease beginning in the infantile, late infantile, juvenile or adult periods. The juvenile form of Batten disease associated with the CLN3 gene is the focus of Beyond Batten Disease Foundation. For a more detailed look at which forms of Batten are associated with which genes, see Table 2).

CLN Gene Defects

Classic Name Gene What does this gene make? Reported forms and age of onset
Infantile BD CLN1 or PPT1 Soluble lysosomal enzyme (palmitoyl protein thioesterase 1) CLN1 disease, infantileCLN1 disease, late infantileCLN1 disease, juvenileCLN1 disease, adult
Late infantile BD CLN2 or TPP1 Soluble lysosomal enzyme (tripeptidyl peptidase 1) CLN2 disease, late infantileCLN2 disease, juvenile
Juvenile BD CLN3 Lysosomal & multi-organelle transmembrane protein (CLN3) CLN3 disease, juvenileCLN3 disease, adult
Adult BD (or Parry or Kufs type A) CLN4 or DNAJC5 Soluble cysteine string protein alpha (CSPa) chaperone protein affecting synapses (CSPa) CLN4 disease, adult autosomal dominant
Variant late infantile BD CLN5 Soluble lysosomal protein, but not an enzyme (CLN5) CLN5 disease, late infantileCLN5 disease, juvenileCLN5 disease, adult
Variant late infantile BD CLN6 Transmembrane protein, Endoplasmic Reticulum (ER) (CLN6) CLN6 disease, late infantile
Adult, Kufs CLN6 disease, adult Kufs type A
Variant late infantile BD CLN7 or MFSD8 Major facilitator superfamily domain containing protein 8, Transmembrane protein; Endolysosomal transporter (CLN7/MFSD8) CLN7 disease, late infantile
Variant late infantile BD CLN8 Transmembrane protein; ER, ER-Golgi intermediate complex (CLN8) CLN8 disease, late infantileCLN8 disease, EPMR
Congenital BD CLN10 or CTSD Soluble lysosomal enzyme (Cathepsin D) CLN10 disease, congenitalCLN10 disease, late infantileCLN10 disease, juvenileCLN10 disease, adult
CLN11 or GRN Progranulin CLN11 disease, adultHeterozygous mutations cause frontotemporal lobar dementia
CLN12 or ATP13A2 P-type ATPase CLN12 disease, juvenileMutations also cause Kufor-Rakeb syndrome
Adult onset BD (or Kufs Type B) CLN13 or CTSF Soluble lysosomal enzyme (Cathepsin F) CLN13 disease, adult Kufs type B
CLN14 or KCTD7 Potassium channel tetramerization domain-containing protein 7 CLN14 disease, infantileMutation also causes progressive myoclonic epilepsy-3

Table 2: adapted from Neuronal ceroid lipofuscinosis: impact of recent genetic advances and expansion of the clinicopathologic spectrum. Curr Neurol. Neurosci Rep. 2013 Aug;13(8):366.8

 

Are there any treatments for the CLN3 form of juvenile Batten disease?

 

Seizures can be reduced or controlled with anticonvulsant drugs, and psychiatric and motor problems can be managed [with medication] as they arise. Physical therapy and occupational therapy may help patients retain motor functioning as long as possible. As yet, there are no approved treatments for the CLN3 form of Batten disease.9,10,11 However, the laboratory bench to patient bedside train of activity is filling up and moving fast (see Table 3).

Who What How StatusTime to Trial
AbeonaGene Therapy to deliver CLN3 geneAAV9/Plasma delivery“May” be moving program to AIM™ capsid AAV vector, less immunogenic, selectively target CNSLess than 5 years
AmicusGene Therapy to deliver CLN3 geneAAV9/Intrathecal DeliveryPreparing for Phase III trial 2021
AmylyxEnhance mitochondrial (cell battery) function SPB/TUDCA small molecule to cross blood brain barrierEarly laboratory development To be determined
BBDF/TheranexusTriple action - ganglioside inhibition to prevent toxic waste build-up, TFEB activation to clear toxic waste build-up, and anti-inflammatory to decelerate neurodegenerationWeekly IV infusion and daily pill combination therapyInvestigational New Drug Application to be filed2021
Calporta/MerckSingle action TRPML-agonist TFEB Activation to clear toxic waste build-upOral suspension or pillsInvestigational New Drug preparation studies2-3 years
Duke UCLN3+ stem cell transplantationUmbilical cord blood translplantation following bone marrow ablation0.5-5.5 years post-transplantation – undeterminable outcomesOngoing
EvoxExosome deliveryExosome delivery of ProteinEarly laboratory developmentTo be determined
Groh and Martini -University Hospital WürzburgAttenuate chronic inflammation responsible for the acceleration of diseaseRepurposing oral immunomodulatory agents used to treat Multiple SclerosisEarly laboratory developmentTo be determined
IonisAntisense Oligonucleotides Anticipated to be oral administrationLaboratory developmentTo be determined
ModernamRNATo be DeterminedLaboratory development To be Determined
Polaryx Single action TFEB activationOral administration 2x per dayFDA IND approved April 20202021
CerevelCyclic adenosine monophosphate (cAMP) is a second messenger regulating neuroinflammation and neuronal survivalPhosphodiesterase‐4 (PDE4) inhibitorsTo be announcedTo be determined

Table 3

Are more treatments on the horizon?

Recent developments in gene therapy, retinal gene therapy, small molecules that cross the blood brain barrier, and stem cell extraction and delivery together with a more advanced understanding of lysosomal biology, cellular trafficking and mitochondrial function, all contribute to the list of emerging therapies to treat CLN3 (Table 3). Beyond Batten Disease Foundation is spearheading a global effort, laying the groundwork for the translation of these and other emerging discoveries into potential medicines. We are looking for more to happen in the fields of exosomes, nutridementia, and mRNA therapeutics. See our research strategy.

 

References

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