Is there any treatment?
As yet, no specific treatment is known that can halt or reverse the symptoms of juvenile Batten (CLN3) disease. In April 2017 the FDA approved Brineura™ as a treatment for late infantile Batten (CLN2) disease. Gene therapy is under preclinical investigation for CLN1, CLN2, CLN3, CLN6 and CLN7 forms of Batten disease. For all forms, seizures can be reduced or controlled with anticonvulsant drugs, and psychiatric and motor problems can be managed with medication. Physical therapy and occupational therapy may help patients retain motor functioning as long as possible
What is the prognosis?
Over time, affected children suffer loss of their sight, mental impairment, worsening seizures, and progressive loss of motor skills. Eventually, those with Batten disease become bedridden, require 24-hour care, and die prematurely. How quickly symptoms develop and the length of the course of disease depends on symptom onset (classic forms of Batten).
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 |
What governs the age of onset?
Juvenile Batten disease was named after Frederick Batten, MA, MD, FRCP, when he reported on two sisters with the disease in 1903. 1, 2 As various forms of Batten were discovered, each was named according to its age of onset (Classic forms of Batten). This was very simple when there were only four known forms [infantile, late infantile, juvenile and adult]. However, several variant late forms were discovered complicating the matter. It wasn’t until the first genes associated with Batten disease were discovered that researchers learned that different mistakes in the same gene can result the same disease with various ages of onset. 4, 6 In other words, mistakes in the CLN1 gene can cause disease beginning in the infantile, late infantile, juvenile or adult periods (CLN Gene Defects).
Juvenile Batten disease, the focus of Beyond Batten Disease Foundation, is also called CLN3 disease. Children with CLN3 disease almost always develop symptoms in the juvenile period.5
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 However, the laboratory bench to patient bedside train of activity is filling up and moving fast (see Table 3).
| Who | What | How | Status | Time to Trial |
|---|---|---|---|---|
| Abeona | Gene Therapy to deliver CLN3 gene | AAV9/Plasma delivery | Moving program to AIM™ capsid AAV vector, less immunogenic, selectively target CNS | Less than 5 years |
| Amicus | Gene Therapy to deliver CLN3 gene | AAV9/Intrathecal Delivery | Preparing for Phase III trial | 2021 |
| Amylyx | Enhance mitochondrial (cell battery) function | SPB/TUDCA small molecule to cross blood brain barrier | Early laboratory development | To be determined |
| BBDF/Theranexus BBDF/Theranexus | Triple action - ganglioside inhibition to prevent toxic waste build-up, TFEB activation to clear toxic waste build-up, and anti-inflammatory to decelerate neurodegeneration | Weekly IV infusion and daily pill combination therapy | Investigational New Drug Application filed April 3, 2020 | 2020 |
| Calporta/Merck | Single action TRPML-agonist TFEB Activation to clear toxic waste build-up | Oral suspension or pills | Investigational New Drug preparation studies | 2-3 years |
| Circumvent | Lipid metabolism | TBD | Early laboratory development | To be determined |
| Duke U/The Mark Foundation | CLN3+ stem cell transplantation | Umbilical cord blood translplantation following bone marrow ablation | 0.5-5.5 years post-transplantation – undeterminable outcomes | OngoingOngoing |
| Exicure | gold nanoparticle-oligonucleotide complexes to create and control CLN3 gene expression | Nanoparticle delivery of DNA | Early laboratory development | To be determined |
| Groh and Martini -University Hospital Würzburg | Attenuate chronic inflammation responsible for the acceleration of disease | Repurposing oral immunomodulatory agents used to treat Multiple Sclerosis | Early laboratory development | To be determined |
| Healx | Using AI to find new links between existing drugs and CLN3 disease | Administration will depend on what is discovered through AI | Software and search methods currently under development | To be determined |
| Ionis | Antisense Oligonucleotides | Anticipated to be oral administration | Laboratory development | To be determined |
| Orphion | Gene Therapy to deliver CLN3 gene | Retinal gene therapy for the rescue of retinal cells (vision) | Laboratory development | 3-5 years |
| Polaryx | Single action TFEB activation | Oral administration 2x per day | FDA IND approved April 2020 | 2021 |
| Recursion Pharmaceuticals | Using AI to find new links between existing drugs and CLN3 disease | Administration will depend on what is discovered through AI | To be announced | To be determined |
| University of Nebraska | Cyclic adenosine monophosphate (cAMP) is a second messenger regulating neuroinflammation and neuronal survival | Phosphodiesterase‐4 (PDE4) inhibitors | To be announced | To be determined |
| Mass Gen Hosp/Harvard U | Gene Therapy to deliver CLN3 gene | Retinal gene therapy for the rescue of retinal cells (vision) | Early Laboratory development | To be determined |
Are 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
- Mole SE, Williams RE, Goebel HH, editors. The Neuronal Ceroid Lipofuscinoses (Batten Disease) Oxford University Press; Oxford. 2011.
- Batten FE. Cerebral degeneration with symmetrical changes in the maculae in two members of a family. Trans Opth Soc UK. 1903;23:386-390.
- Batten FE. Family cerebral degeneration with macular change (so-called juvenile form of family amarautic idiocy). Q J Med. 1914;7:444-454.
- International Batten Disease Consortium. Isolation of a novel gene underlying Batten disease, CLN3. Cell 82. 1995;949-957.
- NCL Resource: A Gateway for Batten Disease [Internet]. London: University College London; Available from: http://www.ucl.ac.uk/ncl/batten.html.
- Vesa J, Hellsten E, Verkruyse LA, et al. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature. 1995 Aug 17;376(6541):584-7.
- Beck-Wodl S, Harzer K, Sturm M, et al. Homozygous TBC1-domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease- a new type of neuronal ceroid lipofuscinosis (CLN15)? Acta Neuropthol Commun. 2018 Dec 27;6(1):145.
- Cotman SL, Karaa A, Staropoli JF, et al. Neuronal ceroid lipofuscinosis: impact of recent genetic advances and expansion of the clinicopathologic spectrum. Curr Neurol. Neurosci Rep. 2013 Aug;13(8):366.
- Ostergaard JR. Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights. Degener Neurol Neuromuscul Dis. 2016. Aug 1;6:73-83.
- Kohlschutter A, Schulz A, Bartsch U, et al. Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs. 2019. Apr;33(4):315-325.