Batten disease

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Batten disease
Other namesSpielmeyer–Vogt–Sjögren–Batten disease, Batten–Mayou disease, Vogt–Spielmeyer disease
Specialty Endocrinology
Usual onset5 to 10 years old [1]
CausesGenetic [1]
Frequency2 to 4 per 100,000 births in the US [1]

Batten disease is a fatal disease of the nervous system that typically begins in childhood. [1] Onset of symptoms is usually between 5 and 10 years of age. [1] Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs). [1]

Contents

Although Batten disease is usually regarded as the juvenile form of NCL (or "type 3"), some physicians use the term Batten disease to describe all forms of NCL. Historically, the NCLs were classified by age of disease onset as infantile NCL (INCL), late infantile NCL (LINCL), juvenile NCL (JNCL) or adult NCL (ANCL). [2] At least 20 genes have been identified in association with Batten disease, but juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in Battenin, the protein encoded by the CLN3 gene. [3] [4] It was first described in 1903. [1]

Signs and symptoms

Signs and symptoms of the disorder usually appear around ages 5–10 years, with gradual onset of vision problems or seizures. [5] Early signs may be subtle personality and behavioral changes, slow learning or regression, repetitive speech or echolalia, clumsiness or stumbling. Slowing head growth in the infantile form, poor circulation in lower extremities (legs and feet), decreased body fat and muscle mass, curvature of the spine, hyperventilation and/or breath-holding spells, teeth grinding and constipation may occur. [6]

Over time, affected children experience mental impairment, worsening seizures and progressive loss of sight, speech and motor skills. Batten disease is a terminal disease; life expectancy varies depending on the type or variation. [7] [8]

Females with juvenile Batten disease show first symptoms a year later than males, but on average die a year sooner. [9]

Cause

NCLs are a family of diseases that are inherited in an autosomal recessive manner. Collectively referred to as Batten disease, NCLs are responsible for most paediatric neurodegenerative diseases. The specific type of NCL is characterized by the age of symptomatic onset and genetic mutation involved. Currently, mutations in ten genes are believed to lead to the development of Batten disease; "the incidence is as high as one in 12,500 live births". [10]

Batten disease has an autosomal recessive pattern of inheritance. Autorecessive.svg
Batten disease has an autosomal recessive pattern of inheritance.

NCL diseases

Juvenile NCL: CLN3 mutation

The CLN3 gene is located on the short arm of chromosome 16 at gene position 12.1 (16p12.1), and mutations within this gene are the major cause of juvenile NCL. More specifically, 73% of Batten disease cases are due to a 1.02-kb deletion within this gene, CLN3, which causes a frameshift which produces a truncated mutant gene product of only 181 amino acids in length when compared to the wild-type gene product of 438 amino acids in length. Normal-functioning CLN3 encodes for a hydrophobic transmembrane protein that is mainly localized to the lysosome; however, the 181 amino acid mutant gene product was instead found to primarily localize to the endoplasmic reticulum and Golgi apparatus. The precise function of the CLN3 gene product remains unknown. [10]

Diagnosis

Batten disease is rare; misdiagnosis may lead to increased medical expenses, family stress, and the chance of using incorrect forms of treatment, which may exacerbate the patient's condition. Nevertheless, Batten disease can be diagnosed if properly detected. Vision impairment is the most common observable symptom of the disease. Partial or complete loss of vision often develops in patients who have childhood forms of Batten disease, while it is usually preserved in those with adult-onset Batten disease. [13] Children or adults suspected of having Batten disease should initially see an optometrist or ophthalmologist. A fundus eye examination that aids in the detection of common vision impairment abnormalities, such as granularity of the retinal pigment epithelium in the central macula will be performed. [14] Though it is also seen in a variety of other diseases, a loss of ocular cells is a warning sign of Batten disease. If Batten disease is the suspected diagnosis, a variety of tests is conducted to help accurately confirm the diagnosis, including:

Treatment

Batten disease is a terminal illness; the FDA has approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. Human clinical trials of a gene therapy for the CLN5 variant of Batten disease began at the University of Rochester in 2022. [16] Palliative treatment is symptomatic and supportive. One drug, an antisense oligonucleotide, milasen, [17] described in The New England Journal of Medicine , [18] is believed to be the first "custom" treatment for a genetic disease. It is named after Mila Makovec, the only patient who may ever take it. [19]

History

Batten disease is named after the British pediatrician Frederick Batten, who first described it in 1903. [20] [21] Also known as Spielmeyer–Vogt–Sjögren–Batten disease, it is the most common form of a group of disorders called neuronal ceroid lipofuscinosis (NCL). Although Batten disease is usually regarded as the juvenile form of NCL, some physicians use the term Batten disease to describe all forms of NCL. [6]

Research

Memorial sculpture in Progress Frenchman's Bay East Park, Pickering, Ontario, Canada, dedicated to the children who have lost or will lose their lives to Batten disease Batten Disease Memorial Sculpture.jpg
Memorial sculpture in Progress Frenchman's Bay East Park, Pickering, Ontario, Canada, dedicated to the children who have lost or will lose their lives to Batten disease

In June 1987, a phase-I clinical trial was launched at Weill Cornell Medical College of Cornell University to study a gene therapy method for treatment of the signs and symptoms of LINCL. The experimental drug works by delivering a gene transfer vector called AAV2CUhCLN2 to the brain. [22] Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. [23]

Researchers believe the neurological deficits common in JNCL could be due to overactive AMPA receptors in the cerebellum. To test this hypothesis, researchers administered AMPA antagonist drugs into affected mice. The motor skills of the affected mice showed significant improvement after the antagonist treatment, which supported the hypothesis that the neurological deficits in JNCL are due to overactive AMPA receptors. This research could eventually help to alleviate neurological deficits of JNCL in humans. [24]

In November 2006, after receiving FDA clearance, neurosurgeon Nathan Selden, pediatrician Bob Steiner, and colleagues at Doernbecher Children's Hospital at Oregon Health and Science University began a clinical study in which purified neural stem cells were injected into the brain of Daniel Kerner, a six-year-old child with Batten disease, who had lost the ability to walk and talk. This patient was the first of six to receive the injection of a stem cell product from StemCells Inc., a Palo Alto biotech company. These are believed to be the first-ever transplants of fetal stem cells into the human brain. [25] By early December, the child had recovered well enough to return home, and some signs of speech returning were reported. [26] The main goal of phase-I clinical trials, however, was to investigate the safety of transplantation. Overall, the phase-I data demonstrated that high doses of human neural stem cells, delivered by a direct transplantation procedure into multiple sites within the brain, followed by 12 months of immunosuppression, were well tolerated by all six patients enrolled in the trial. [27] [28] The patients' medical, neurological, and neuropsychological conditions, following transplantation, appeared consistent with the normal course of the disease. [28]

In 2010, Cherie and Jim Flores donated $2 million, the biggest gift in Batten disease research history, and the Beyond Batten Disease Foundation contributed $500,000 to establish laboratories for Italian researchers Drs. Ballabio, Sardiello and their colleagues at the Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital.

During 2011, the first controlled clinical trials began with the University of Rochester for a treatment for Batten Disease. The trial included 30 patients who were experiencing signs of the disease in the hope of slowing its progress. [28] [29]

In November 2013, Weill Medical College of Cornell University began recruiting participants for a safety study of a gene transfer vector, described as a non-randomised safety and efficacy trial. As part of a trial began by University of Rochester in March 2014. Mycophenolate mofetil is being tested to determine its efficacy and safety using a gene transfer vector. [30] [29] [31]

In April 2019, Haney et al. delivered brain soluble lysosomal enzyme TPP1 to treat the disease. Results showed an increased survival rate in late-infantile neruonal ceroid lipofuscinosis (LINCL) mice following treatment. Treatment also showed decreased neuroinflammation, a common side effect that leads to neuronal damage and death, compared to that of mice treated with just saline. [32]

In complex diseases such as Batten, therapies that address multiple aspects of the disease at the same time have the potential for higher impact than those focusing on one aspect. "The use of several treatment strategies might offer additional benefits to patients with neurodegenerative disease, but the benefits of this approach must be weighed carefully against the additional adverse effects that combined treatments might bring," the researchers wrote. The medical team also noted that "over the past two decades, scientists and clinicians within the Batten disease community have worked to ensure that tools are in place to enable progress towards effective treatments at an unprecedented pace. "Recent progress in Batten disease research offers hope that efficient and targeted therapies will be available soon," the researchers said, noting that "the Batten disease research community is becoming a model of how effective, efficient rare disease research can be accomplished by working together."[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Neuronal ceroid lipofuscinosis</span> Medical condition

Neuronal ceroid lipofuscinosis is a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.

Infantile neuronal ceroid lipofuscinoses (INCL) or Santavuori disease or Hagberg–Santavuori disease or Santavuori–Haltia disease or Infantile Finnish type neuronal ceroid lipofuscinosis or Balkan disease is a form of NCL and inherited as a recessive autosomal genetic trait. The disorder is progressive, degenerative and fatal, extremely rare worldwide – with approximately 60 official cases reported by 1982.

<span class="mw-page-title-main">Battenin</span> Protein found in humans

Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16. Battenin is not clustered into any Pfam clan, but it is included in the TCDB suggesting that it is a transporter. In humans, it belongs to the atypical SLCs due to its structural and phylogenetic similarity to other SLC transporters.

Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).

<span class="mw-page-title-main">Palmitoyl(protein) hydrolase</span> Class of enzymes

Palmitoyl protein hydrolase/thioesterases is an enzyme (EC 3.1.2.22) that removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. It catalyzes the reaction

<span class="mw-page-title-main">Tripeptidyl peptidase I</span> Protein-coding gene in the species Homo sapiens

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene, also known as CLN2. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late-infantile neuronal ceroid lipofuscinosis.

<span class="mw-page-title-main">CLN6</span> Protein-coding gene in humans

Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.

<span class="mw-page-title-main">CLN5</span> Protein-coding gene in humans

Ceroid-lipofuscinosis neuronal protein 5 is a protein that in humans is encoded by the CLN5 gene.

<span class="mw-page-title-main">CLN8</span> Protein-coding gene in humans

Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.

<span class="mw-page-title-main">PPT1</span> Protein-coding gene in the species Homo sapiens

Palmitoyl-protein thioesterase 1 (PPT-1), also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene.

<span class="mw-page-title-main">Jansky–Bielschowsky disease</span> Medical condition

Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown; however, NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.

A Finnish heritage disease is any genetic disease or disorder that is significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Northern Sweden (Meänmaa) and Northwest Russia. There are 36 rare diseases regarded as Finnish heritage diseases. The diseases are not restricted to Finns; they are genetic diseases with far wider distribution in the world, but due to founder effects and genetic isolation they are more common in Finns.

<span class="mw-page-title-main">Northern epilepsy syndrome</span> Medical condition

Northern epilepsy syndrome (NE), or progressive epilepsy with mental retardation (EPMR), is a subtype of neuronal ceroid lipofuscinosis and a rare disease that is regarded as a Finnish heritage disease. Unlike most Finnish heritage diseases, this syndrome has been reported only in Finland. The disease is characterized by seizures in early childhood that progressively get worse until after puberty. Once the onset of seizures occurs, mental degradation is seen. This continues into adulthood, even after seizure frequency has decreased. The cause of the disease is a missense mutation on chromosome 8. The creation of a new protein occurs, and the lipid content of the brain is altered because of it. The ratio of the mutation carriers is 1:135. There is nothing that has been found to stop the progression of the disease, but symptomatic approaches, such as the use of benzodiazepines, have helped control seizures.

<span class="mw-page-title-main">MFSD8</span> Protein-coding gene in the species Homo sapiens

Major facilitator superfamily domain containing 8 also called MFSD8 is a protein that in humans is encoded by the MFSD8 gene. MFSD8 is an atypical SLC, thus a predicted SLC transporter. It clusters phylogenetically to the Atypical MFS Transporter family 2 (AMTF2).

Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs) or Batten disease. NCLs are broadly described to create problems with vision, movement and cognitive function. Among all NCLs diseases, Kufs is the only one that does not affect vision, and although this is a distinguishing factor of Kufs, NCLs are typically differentiated by the age at which they appear in a patient.

Cerliponase alfa, marketed as Brineura, is an enzyme replacement treatment for Batten disease, a neurodegenerative lysosomal storage disease. Specifically, Cerliponase alfa is meant to slow loss of motor function in symptomatic children over three years old with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency, a soluble lysosomal enzyme deficiency. Approved by the United States Food and Drug Administration (FDA) on 27 April 2017, this is the first treatment for a neuronal ceroid lipofuscinosis of its kind, acting to slow disease progression rather than palliatively treat symptoms by giving patients the TPP1 enzyme they are lacking.

Sara Elizabeth Mole Crowley is a Professor of Molecular Cell Biology and Provost's Envoy for Gender Equality at University College London and the Great Ormond Street Hospital. She works on diseases caused by genetic changes, in particular neurodegenerative diseases that impact children.

Erika F. Augustine is an Associate Chief Science Officer and Director of the Clinical Trials Unit at Kennedy Krieger Institute. She was previously an Associate Professor of Neurology and Pediatrics at the University of Rochester Medical Center in Rochester, New York. Augustine co-directed the University of Rochester Batten Center, and was the associate director of both the Center for Health and Technology and the Udall Center of Excellence in Parkinson's Disease Research. Augustine's clinical research and medical practice specialize in pediatric movement disorders. She leads clinical trials for Batten diseases, a group of rare pediatric neurodegenerative disorders, and she has developed a novel telemedicine model to increase the efficacy of remote care for patients with rare diseases.

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References

  1. 1 2 3 4 5 6 7 "Batten Disease Fact Sheet | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 30 November 2020.
  2. ↑ Hobert JA, Dawson G (October 2006). "Neuronal ceroid lipofuscinoses therapeutic strategies: past, present and future". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1762 (10): 945–53. doi: 10.1016/j.bbadis.2006.08.004 . PMID   17049436.
  3. ↑ Rakheja D, Narayan SB, Bennett MJ (September 2007). "Juvenile neuronal ceroid-lipofuscinosis (Batten disease): a brief review and update". Current Molecular Medicine. 7 (6): 603–8. doi:10.2174/156652407781695729. PMID   17896996.
  4. ↑ Cooper JD (June 2008). "Moving towards therapies for juvenile Batten disease?". Experimental Neurology. 211 (2): 329–31. doi:10.1016/j.expneurol.2008.02.016. PMID   18400221. S2CID   32126291.
  5. ↑ Basu, Ishita; Perry, Michael (2021). "2. Initial assessment of the "Head and Neck" patient". In Perry, Michael (ed.). Diseases and Injuries to the Head, Face and Neck: A Guide to Diagnosis and Management. Switzerland: Springer. p. 109. ISBN   978-3-030-53098-3.
  6. 1 2 Ostergaard, JR (2016). "Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights". Degenerative Neurological and Neuromuscular Disease. 6: 73–83. doi: 10.2147/DNND.S111967 . PMC   6053093 . PMID   30050370.
  7. ↑ "Batten Disease - National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov.
  8. ↑ Mole, Sara E.; Williams, Ruth E. (1993). "Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY". GeneReviews. University of Washington, Seattle. PMID   20301601.
  9. ↑ Cialone J, Adams H, Augustine EF, et al. (May 2012). "Females experience a more severe disease course in Batten disease". Journal of Inherited Metabolic Disease. 35 (3): 549–55. doi:10.1007/s10545-011-9421-6. PMC   3320704 . PMID   22167274.
  10. 1 2 Jill M. Weimer; Elizabeth Kriscenski-Perry; Yasser Elshatory; David A. Pearce (2002). "The Neuronal Ceroid Lipofuscinoses: Mutations in Different Proteins Result in Similar Disease". NeuroMolecular Medicine. 1 (2): 111–124. doi:10.1385/nmm:1:2:111. PMID   12025857. S2CID   33921126.
  11. 1 2 3 4 5 6 7 8 9 10 Jalanko, Anu; Braulke, Thomas (2009). "Neuronal ceroid lipofuscinoses". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1793 (4): 697–709. doi: 10.1016/j.bbamcr.2008.11.004 . PMID   19084560.
  12. ↑ "Warren Recognizes Batten Disease Awareness Day". YouTube . June 4, 2018. Archived from the original on 2021-12-21. Retrieved May 30, 2020.
  13. ↑ Simonati, A; Williams, RE (2022). "Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview". Frontiers in Neurology. 13: 811686. doi: 10.3389/fneur.2022.811686 . PMC   8961688 . PMID   35359645.
  14. ↑ Bozorg, S; Ramirez-Montealegre, D; Chung, M; Pearce, DA (July 2009). "Juvenile neuronal ceroid lipofuscinosis (JNCL) and the eye". Survey of Ophthalmology. 54 (4): 463–71. doi:10.1016/j.survophthal.2009.04.007. PMC   4139962 . PMID   19539834.
  15. 1 2 3 4 5 6 "Noah's Hope - Causes and Symptoms of Batten Disease". www.noahshope.com. Archived from the original on 2016-11-23. Retrieved 2016-11-22.
  16. ↑ Biochemistry, Department of (2022-08-02). "Trial of world-first gene therapy for Batten disease". www.otago.ac.nz. Retrieved 2024-04-13.
  17. ↑ Chen, Angus (October 15, 2019). "A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine" . Retrieved May 30, 2020.
  18. ↑ Kim, Jinkuk; Hu, Chunguang; Moufawad El Achkar, Christelle; Black, Lauren E.; Douville, Julie; Larson, Austin; Pendergast, Mary K.; Goldkind, Sara F.; Lee, Eunjung A.; Kuniholm, Ashley; Soucy, Aubrie; Vaze, Jai; Belur, Nandkishore R.; Fredriksen, Kristina; Stojkovska, Iva; Tsytsykova, Alla; Armant, Myriam; Didonato, Renata L.; Choi, Jaejoon; Cornelissen, Laura; Pereira, Luis M.; Augustine, Erika F.; Genetti, Casie A.; Dies, Kira; Barton, Brenda; Williams, Lucinda; Goodlett, Benjamin D.; Riley, Bobbie L.; Pasternak, Amy; et al. (2019). "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease". New England Journal of Medicine. 381 (17): 1644–1652. doi:10.1056/NEJMoa1813279. PMC   6961983 . PMID   31597037.
  19. ↑ Kim, J; Hu, C; Moufawad El Achkar, C; Black, LE; Douville, J; Larson, A; Pendergast, MK; Goldkind, SF; Lee, EA; Kuniholm, A; Soucy, A; Vaze, J; Belur, NR; Fredriksen, K; Stojkovska, I; Tsytsykova, A; Armant, M; DiDonato, RL; Choi, J; Cornelissen, L; Pereira, LM; Augustine, EF; Genetti, CA; Dies, K; Barton, B; Williams, L; Goodlett, BD; Riley, BL; Pasternak, A; Berry, ER; Pflock, KA; Chu, S; Reed, C; Tyndall, K; Agrawal, PB; Beggs, AH; Grant, PE; Urion, DK; Snyder, RO; Waisbren, SE; Poduri, A; Park, PJ; Patterson, A; Biffi, A; Mazzulli, JR; Bodamer, O; Berde, CB; Yu, TW (24 October 2019). "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease". The New England Journal of Medicine. 381 (17): 1644–1652. doi:10.1056/NEJMoa1813279. PMC   6961983 . PMID   31597037. S2CID   204030052.
  20. ↑ synd/7 at Who Named It?
  21. ↑ Batten FE (1902). "Cerebral degeneration with symmetrical changes in the maculae in two members of a family". Transactions of the Ophthalmological Societies of the United Kingdom. 23: 386–90.
  22. ↑ Clinical trial number NCT00151216 for "Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis" at ClinicalTrials.gov
  23. ↑ Worgall S, Sondhi D, Hackett NR, et al. (May 2008). "Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA". Human Gene Therapy. 19 (5): 463–74. CiteSeerX   10.1.1.553.872 . doi:10.1089/hum.2008.022. PMID   18473686.
  24. ↑ Kovács, Attila D.; Pearce, David A. (2008-01-01). "Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease". Experimental Neurology. The Role of α-synuclein in the Pathogenesis of Parkinson's Disease / Gene Therapy for Parkinson's. 209 (1): 288–291. doi:10.1016/j.expneurol.2007.09.012. PMC   4418195 . PMID   17963751.
  25. ↑ "A stem cell first at OHSU Archived 2012-02-06 at the Wayback Machine " The Portland Tribune , Nov 24, 2006
  26. ↑ "First recipient of new Batten's disease stem cell cure well enough to go home • PET". PET. 9 June 2009. Retrieved 22 June 2022.
  27. ↑ "A Phase I Study of the Safety and Preliminary Effectiveness of Human CNS Stem Cells (HuCNS-SC) in Patients With Neuronal Ceroid Lipofuscinosis Caused by Palmitoyl Protein Thioesterase 1 (PPT1) or Tripeptidyl Peptidase 1 (TPP-I) Deficiency". clinicaltrials.gov. 13 January 2015.
  28. 1 2 3 Selden, NR; Al-Uzri, A; Huhn, SL; Koch, TK; Sikora, DM; Nguyen-Driver, MD; Guillaume, DJ; Koh, JL; Gultekin, SH; Anderson, JC; Vogel, H; Sutcliffe, TL; Jacobs, Y; Steiner, RD (June 2013). "Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis". Journal of Neurosurgery. Pediatrics. 11 (6): 643–52. doi:10.3171/2013.3.PEDS12397. PMID   23581634.
  29. 1 2 Augustine, Erika (7 May 2019). "Phase II, Randomized, Placebo Controlled Trial of the Safety and Tolerability of Mycophenolate in Children With Juvenile Neuronal Ceroid Lipofuscinosis". clinicaltrials.gov.
  30. ↑ Augustine, EF; Beck, CA; Adams, HR; Defendorf, S; Vierhile, A; Timm, D; Weimer, JM; Mink, JW; Marshall, FJ (2019). "Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis)". JIMD Reports. 43: 117–124. doi:10.1007/8904_2018_113. ISBN   978-3-662-58613-6. PMC   6323012 . PMID   29923092.
  31. ↑ Sondhi, Dolan; Kaminsky, Stephen M.; Hackett, Neil R.; Pagovich, Odelya E.; Rosenberg, Jonathan B.; De, Bishnu P.; Chen, Alvin; Van de Graaf, Benjamin; Mezey, Jason G.; Mammen, Grace W.; Mancenido, Denesy; Xu, Fang; Kosofsky, Barry; Yohay, Kaleb; Worgall, Stefan; Kaner, Robert J.; Souwedaine, Mark; Greenwald, Bruce M.; Kaplitt, Michael; Dyke, Jonathan P.; Ballon, Douglas J.; Heier, Linda A.; Kiss, Szilard; Crystal, Ronald G. (2 December 2020). "Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2". Science Translational Medicine. 12 (572): eabb5413. doi:10.1126/scitranslmed.abb5413. ISSN   1946-6234. PMC   8056991 . PMID   33268510.
  32. ↑ Haney, Matthew J.; Klyachko, Natalia L.; Harrison, Emily B.; Zhao, Yuling; Kabanov, Alexander V.; Batrakova, Elena V. (June 2019). "TPP1 Delivery to Lysosomes with Extracellular Vesicles and their Enhanced Brain Distribution in the Animal Model of Batten Disease". Advanced Healthcare Materials. 8 (11): 1801271. doi:10.1002/adhm.201801271. ISSN   2192-2640. PMC   6584948 . PMID   30997751.
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