BGT-PD for Parkinson’s Disease (PD)

BGT-PD is a first-in-class investigational AAV2 gene therapy designed to rebalance dopamine transporter (DAT) activity in idiopathic PD patients following a single intra-putaminal injection. Initial proof-of-concept data indicated a profound effect of the treatment in suppressing levodopa-induced dyskinesia (LID), a prominent side effect of chronic levodopa therapy. Additional therapeutic benefits of this approach, including disease-modifying effects, are under investigation.

The AAV2 capsid was selected for its previous success in PD and in other localised neurological disorders such as aromatic L-amino acid decarboxylase (AADC) deficiency. BGT-PD relies on the same gene therapy vector used in the BGT-DTDS program.

Parkinson’s Disease (PD)

Disease Characteristics: PD is a progressive neurodegenerative disorder characterised by gradual loss of dopamine-producing brain cells resulting in progressive impairment of motor function (tremors, muscle rigidity, bradykinesia and postural instability) as well as non-motor function (e.g., cognitive impairment, mood alterations, sleep disturbance).

Several factors can contribute to reduced DAT activity in PD patients including dopaminergic neurons loss and early synaptic dysfunction, activation of compensatory mechanisms in the pre-motor PD stage resulting in DAT down-regulation, as well as pathological variants of the SLC6A3 gene or mutation in PD-linked genes (e.g., LRRK2, SNCA, Parkin) which can result in impaired DAT expression or function.

Unmet Needs: Standard of care for PD patients involves a multidisciplinary approach to manage and alleviate symptoms and improve overall quality of life. There are no approved disease-modifying therapies for PD and levodopa (L-DOPA), a precursor of dopamine, remains the most effective, first-line treatment to control motor symptoms in early disease stages. However, as the disease progresses, chronic treatment with L-DOPA can lead to the development of motor fluctuations and LID in a majority of PD patients, limiting its long-term efficacy.

Epidemiology: Global estimates in 2019 showed over 8.5 million individuals affected by PD. LID is a prevalent and debilitating side effect of chronic levodopa treatment, the current gold-standard for managing PD motor symptoms. Around 50% of PD patients are affected by LID after 5 years of levodopa treatment increasing to up to 90% after 10 years, with current treatment options providing only partial therapeutic benefit on LID.

Program status

We have completed a preclinical proof-of-concept study showing that a single administration of BGT-PD in the putamen of hemiparkinsonian rats rendered dyskinetic had a profound effect on LID compared to vehicle-treated controls, with a magnitude of effect markedly superior to that achieved by existing medication for dyskinesia. Data also indicate a potential effect on non-motor symptoms, with a reduction in anxiety behaviours observed in animals treated with BGT-PD. Building on these compelling findings, we are developing a comprehensive preclinical program to further evaluate the long-term safety and efficacy of BGT-PD as anti-dyskinetic treatment as well as its therapeutic potential as a disease-modifying approach.

BGT-PD relies on the same gene therapy vector used in our BGT-DTDS program, which is being developed concurrently for the treatment of Dopamine Transporter Deficiency Syndrome (DTDS), a rare, monogenic disorder caused by mutations in DAT gene leading to parkinsonism-like clinical features and premature death in childhood/teenage years (see BGT-DTDS program).

BGT-PD publications

Leoni G, Eaglestone S, Shaw L, Gissen P, Rahim A, Waddington S, Kurian M, Lemoine A. 2024. Proof-of-concept efficacy of BGT-PD, a novel AAV-based gene therapy approach for the treatment of Levodopa-Induced Dyskinesia (LID) in Parkinson’s Disease. ASGCT 2024 poster presentation.

Relevant publications

Bu M, Farrer MJ, Khoshbouei H. 2021. Dynamic control of the dopamine transporter in neurotransmission and homeostasis. Npj Parkinson’s Disease. 7:22.

Palermo G, Giannoni S, Bellini G, Siciliano G, Ceravolo R. 2021. Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review. Int. J. Mol. Sci. 22, 11234.

Saari L, Kivinen K, Gardberg M, Joutsa J, Noponen T, Kaasinen V. 2017. Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease. Neurology. 88(15):1461-1467.

Palermo G, Giannoni S, Frosini D, Morganti R, Volterrani D, Bonuccelli U, Pavese N, Ceravolo R. 2020. Dopamine Transporter, Age, and Motor Complications in Parkinson’s Disease: A Clinical and Single-Photon Emission Computed Tomography Study. Mov. Disord. 35(6): 1028–1036.

Reith MEA, Kortagere S, Wiers CE, Sun H, Kurian MA, Galli A, Nora D. Volkow ND, Lin Z. 2022. The dopamine transporter gene SLC6A3: multidisease risks. Molecular Psychiatry. 27: 1031-46.

Ravina B, Marek K, Eberly S, Oakes D, Kurlan R, Ascherio A, Beal F, Beck J, Flagg E, Galpern WR, Harman J, Lang AE, Schwarzschild M, Tanner C, Shoulson I. 2012. Dopamine transporter imaging is associated with long-term outcomes in Parkinson’s disease. Mov. Disord. 27(11):1392-7.

Troiano AR, de la Fuente-Fernàndez R, Sossi V, Schulzer M, Mak E, Ruth TJ, Stoessl AJ. 2009. PET demonstrates reduced dopamine transporter expression in PD with dyskinesias. Neurology. 72 (14).

Tomas D, Stanic D, Chua HK, White K, Boon WC, Horne M. 2016. Restoration of the Dopamine Transporter through Cell Therapy Improves Dyskinesia in a Rat Model of Parkinson’s Disease. PLoS One. 11(4).

Axelsena TM and Woldbye DPD. 2018. Gene Therapy for Parkinson’s Disease, An Update. J Parkinsons Dis. 8(2): 195–215.

More information about PD

Parkinson’s UK https://www.parkinsons.org.uk/

Cure Parkinson’s https://cureparkinsons.org.uk/

The Michael J. Fox Foundation for Parkinson’s Research https://www.michaeljfox.org/