AMT-130 gene therapy slows disease progression in patients with Huntington disease
AMT-130, a gene therapy which uses RNA interference to lower levels of mHTT (mutant huntingtin) protein, has shown promising results in one phase 1/2 study. Based on information from press releases, initial topline results from the European arm of the study indicate that the therapy has the potential to slow disease progression, giving hope to patients with Huntington disease.
The study met its primary endpoint, with a statistically significant 75% slowing of disease progression with high-dose AMT-130 compared with control at 36 months, as measured using the composite Unified Huntington Disease Rating Scale. A secondary endpoint was also met, with high-dose AMT-130 showing a statistically significant 60% slowing of disease progression as measured by Total Functional Capacity. Favorable trends were also found across additional clinical measures of motor and cognitive function, mean cerebrospinal fluid neurofilament light protein (NfL) levels reduced below baseline at 36 months, and the therapy was well tolerated with a manageable safety profile.[109]
A single dose of the drug is expected to last a lifetime. The Food and Drug Administration (FDA) has previously granted AMT-130 breakthrough therapy designation and regenerative medicine advanced therapy designation, programs designed to accelerate the development and review of new drugs. It is anticipated that a biologics license application will be submitted to the FDA in 2026 requesting accelerated approval of the drug.[109][110] AMT-130 currently also has orphan drug designation in Europe.
小结
定义
病史和体格检查
关键诊断因素
- positive family history of Huntington disease
- known expansion of the CAG repeat length at the N-terminal end of the huntingtin gene
- impaired work or school performance
- personality change
- irritability and impulsivity
- chorea
- twitching or restlessness
- loss of coordination
- deficit in fine motor coordination
- slowed rapid (saccadic) eye movements
- motor impersistence
- impaired tandem walking
其他诊断因素
- concentration impairment/task anxiety or apathy
- cognitive decline relative to partner/siblings
- changes in personal habits/hygiene
- disinhibition or unusually anxious behavior
- depression, obsessions, and compulsions
- sleep disturbance
危险因素
- expansion of the CAG repeat length at the N-terminal end of the huntingtin gene
- other genetic factors
- family history
诊断性检查
首要检查
- no initial tests
需考虑的检查
- genetic test for cytosine-adenine-guanine (CAG) repeat expansion
- MRI or CT scan
治疗流程
all patients
撰稿人
作者
Mitsuko Nakajima, MD
Clinical Research Fellow
Huntington's Disease Centre
Queen Square
Institute of Neurology
Department of Neurodegenerative Disease
Russell Square House
London
UK
Disclosures
MN is funded by the clinical fellowship scheme from the Huntington's Disease Society of America, a nonprofit organization that funds research into Huntington disease. There is no contractual agreement to disseminate product information.
Acknowledgements
Dr Mitsuko Nakajima would like to gratefully acknowledge Dr Peter McColgan, Dr Sarah Tabrizi, Dr David Craufurd, Dr Marianne Novak, and Dr Francis Walker, previous contributors to this topic.
Disclosures
FW declared that he had no competing interests. MN is an author of a reference cited in this topic. DC has received fees for advisory board membership from Hoffmann-La Roche Ltd. SJT has received grant funding for her research from CHDI Foundation, the BBSRC, Dementia and Neurodegenerative Disease Network UK, European Huntington’s Disease Network, Huntington’s Disease Association of the UK, the Medical Research Council UK, Takeda Pharmaceuticals, the UCL/UCLH Biomedical Research Center, and the Wellcome Trust. SJT has been on advisory boards or had consultancies with F. Hoffmann-La Roche Ltd, Ixico Technologies, Shire Human Genetic Therapies, Takeda Pharmaceuticals International, and TEVA Pharmaceuticals; all honoraria for these consultancies and advisory boards were paid to UCL. Through the offices of UCL Consultants Ltd, a wholly owned subsidiary of UCL, SJT has undertaken consultancy services for F. Hoffmann-La Roche Ltd and GSK. ST is also an author of references cited in this topic PM declared that he had no competing interests.
Peer reviewers
Adrian Priesol, MD, FRCPC
Instructor
Massachusetts Eye and Ear Infirmary
Harvard Medical School
Boston
MA
Disclosures
AP declares that he has no competing interests.
Tiago Mestre, MD, MSc
Resident Neurology
Neurological Clinical Research Unit
Institute of Molecular Medicine
Lisbon
Portugal
Disclosures
TM declares that he has no competing interests.
Peer reviewer acknowledgements
BMJ Best Practice topics are updated on a rolling basis in line with developments in evidence and guidance. The peer reviewers listed here have reviewed the content at least once during the history of the topic.
Disclosures
Peer reviewer affiliations and disclosures pertain to the time of the review.
References
Key articles
Bean L, Bayrak-Toydemir P; American College of Medical Genetics and Genomics. Standards and guidelines for clinical genetics laboratories, 2014 edition: technical standards and guidelines for Huntington disease. Genet Med. 2014 Dec;16(12):e2.Full text Abstract
Anderson KE, van Duijn E, Craufurd D, et al. Clinical management of neuropsychiatric symptoms of Huntington disease: expert-based consensus guidelines on agitation, anxiety, apathy, psychosis and sleep disorders. J Huntingtons Dis. 2018;7(3):355-66.Full text Abstract
Bachoud-Lévi AC, Ferreira J, Massart R, et al. International guidelines for the treatment of Huntington's disease. Front Neurol. 2019;10:710.Full text Abstract
Quinn L, Kegelmeyer D, Kloos A, et al. Clinical recommendations to guide physical therapy practice for Huntington disease. Neurology. 2020 Feb 4;94(5):217-28.Full text Abstract
Reference articles
A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.
Differentials
- Tardive dyskinesia
- Dentatorubro-pallidoluysian atrophy (DRPLA)
- Neuroacanthocytosis
More DifferentialsGuidelines
- Clinical guidance in neuropalliative care: an AAN position statement
- Clinical recommendations to guide physical therapy practice for Huntington disease
More GuidelinesPatient information
Depression in adults
Huntington’s disease
More Patient information
Log in or subscribe to access all of BMJ Best Practice
Use of this content is subject to our disclaimer