Welcome to the CGTA Research Group
Our name stands for “CNS Gene therapy Translation Acceleration.”
Our goal is to bring gene therapies for rare Central Nervous System diseases into clinical trials and use as quickly and efficiently as possible. Our first project is focused on developing a gene therapy for Huntington’s disease.
LATEST NEWS:
Summer, 2026
Although manuscripts for publication are yet to be written and sent to journals, our project’s final report has been submitted to the National Institute of Neurological Diseases and Stroke (NINDS). The report summarizes the main project outcomes as follows:
- We confirmed and extended the findings of the shorter, previous study using AAV2 regarding the safety of lowering wildtype huntingtin in the primate striatum (Grondin et al., 2012). In the animals in the current study receiving a dose of AAV6 targeting huntingtin into the striatum, the expression of huntingtin protein in those regions was reduced by 40% as measured at the end of a nine-month period. No motor deficits were observed in these recipients by a skilled rater blind to the treatment groups, and no other effects indicative of a safety concern were found.
- Regardless of whether the anti-huntingtin or a comparable inactive payload was given, a high dose of AAV6 delivered to the primate thalamus was not safe. It resulted in serious motor deficits in all animals in both the huntingtin-lowering and control groups, with gross thalamic lesions evident in post-mortem examination of their brains.
- The amount of huntingtin lowering achieved by the AAV6 delivering the shRNA targeting huntingtin did not directly scale with the dose of AAV6. Both the high and a six-fold lower dose of AAV6 resulted in comparable lowering of huntingtin protein production in the thalamus, measured at 52% and 49%, respectively, at the end of the nine-month period.
- The injection into the thalamus of the lower dose of the AAV6 targeting huntingtin, identical to the dose found to be well-tolerated in the striatum, nevertheless resulted in motor deficits in a subset of animals. These adverse effects were significantly milder in the low versus high dose thalamic recipients (p < 0.05) and resolved over time in all but one low dose recipient but they persisted in all high dose recipients.
We recommend proceeding with caution when designing clinical trials seeking to administer AAV preparations into the human thalamus.
Summer, 2025
The 9-month in-life phase of this research has now been completed by all animals. Now, while the data collection from the in-life videos is on-going, the post-mortem analyses of the tissue samples begins.
April, 2024
As of this month, three out of the ten animals in the latest cohort of animals (see update below from March) are now exhibiting some motor deficits contralateral to the infused thalamus. The team remains blinded as to which treatment which animals have received, and the study is on-going, with the terminations of the animals and postmortem analyses planned for the end of summer of 2025.
March, 2024
A poster providing a project update (2nd interim report) from our on-going research was presented at the 19th Annual Huntington’s Disease Therapeutics Conference in Palm Springs, California at the end of February, 2024. Our project investigating the long-term effects of lowering wildtype huntingtin in the brain using shRNA is proceeding using a dose of AAV vector that is the same as the dose that we previously found to be innocuous when delivering AAV2-mediated shRNA delivery to the striatum [Grondin et al, 2012]. To date, five animals have received the AAV6 vector encoding the huntingtin-lowering shRNA and five have received the comparable control vector by a unilateral infusion into the thalamus. So far, out to more than 100 days post-operatively in some animals, no adverse effects of the vector delivery have been observed in any of the animals by veterinary staff blind to which vector was administered to which animal. We will continue to monitor these animals for a total of nine months post-operatively via periodic neurological examinations by trained staff, monitoring of the animals’ food intake and general health, and video tapes of the animals’ behavior. Post-mortem data collection will begin in the fall of 2024.
July, 2023
As noted below, a poster presenting interim results from our on-going research was presented at the 18th Annual Huntington’s Disease Therapeutics Conference in Dubrovnik in April, 2023. The interim results concerned our project investigating the long-term effects of lowering wildtype huntingtin in the brain using shRNA delivered using a viral vector. At the time, the results showed that five out of five animals receiving a huntingtin-lowering vector in the thalamus of the brain had developed motor deficits, while the three animals receiving a control vector had not. As the project has progressed, we now have found that two out of the three animals receiving the control vector later also developed motor deficits. There is a statistically significant difference between the two groups in the severity of their motor deficits (scored on a standardized rating scale by a blinded rater) during the first several months of their in-life period; however, in later months, two of the animals in the control group develop deficits that were just as severe.
Our current working hypothesis is that in addition to whatever effects of huntingtin-lowering are occurring in these animals, there is also a non-specific effect of the AAV6-delivered shRNA, perhaps “mechanistic toxicity” due to the level of shRNA expression, or a delayed immune or inflammatory reaction to the AAV6. We will be continuing our investigation using a lower dose of the AAV vectors (dropping down to a vector load we have found to be innocuous when delivering AAV2-mediated shRNA delivery to the striatum [Grondin et al, 2012]) and we will present further interim results of this long-term study at the next CHDI conference in February. In the meantime, interested parties should be advised that it is premature to make any final conclusions about the safety of lowering wildtype huntingtin in the thalamus based only on our results so far.
April, 2023
We presented interim findings from our study at the 18th Annual CHDI Huntington’s Disease Therapeutics Conference in Dubrovnik, Croatia. See the abstract for poster #1 in the conference materials, or email info@cgtaresearchgroup.org to request details.
December, 2022
We have initiated our main study and now have seven animals in the “in-life” stage of our study plan. Interim results will be presented at upcoming conferences in the spring of 2023.
July, 2021
After unavoidable delays due to the COVID-19 pandemic, we have initiated our study of the safety of long-term huntingtin-lowering in the brain with the delivery of a huntingtin-lowering agent to the thalamus of a pilot animal. The purpose of the pilot is to confirm the activity and the dosage of the agent to be used in the main study that will start later this year.
February, 2020
We have received word from the National Institute of Neurological Disorders and Stroke as follows: “[your] application was reviewed by the National Advisory Neurological Disorders and Stroke Council at its recent meeting. We are pleased to inform you that we anticipate funding this application. Once all pre-award requirements have been met, a notice of grant award will be issued…”
We will provide more details here once this multi-year research project is underway!
Fall, 2019
Our Huntington’s disease-related grant application to the National Institute of Neurological Disorders and Stroke (NINDS) was reviewed, discussed, and favorably scored by the scientific study section in October, 2019. Here’s hoping the NIH budget is sufficient this year for our score to be within the pay line.
Summer, 2019
Our grant application to the National Institute of Neurological Disorders and Stroke (NINDS) was received in good order in June, 2019, and will be reviewed by the Chronic Dysfunction and Integrative Neurodegeneration Study Section on October 15, 2019.
March, 2019:
We are in the process of preparing a grant application for submission to NINDS, regarding huntingtin-lowering. This application will be responsive to the reviews of our latest application (which received positive reviews, but not a sufficiently good priority score to make the funding cut), and also recent findings about the effects of huntingtin-lowering in animals. See the literature review by Kaemmerer and Grondin, just published this month.