Bioviva was at one point developing telomerase gene therapies, work that has transitioned into the medical tourism industry via Integrated Health Systems rather than proceeding towards regulatory approval. The institutional communities of science and funding strongly disapproved of the self-experiment undertaken by the Bioviva founder, and the way that self-experiment was popularized in order to build the company. I think this a pity, given the long history of self-experimentation by noted figures in the scientific community. Nonetheless, we live in an era that frowns upon self-experimentation as a part of the path to progress, and applies very high standards to those who attempt it.
The gene therapies that Bioviva worked upon, and Integrated Health Systems now sells to well-to-do medical tourists, involve localized injection of small amounts of AAV vectors to upregulate expression of telomerase. The alternative option of intravenous injection of large amounts of AAV, in order to reach much of the body in adults, is coming to be looked upon with disfavor in the investment, regulatory, and development communities. This is based on liver toxicity and a few patient deaths at the high doses needed for that mode of administration. Localized injections can use a small fraction of the intravenous injection amount, avoiding issues of toxicity, but are unfortunately still a one-time treatment at present: the immune system will remember the AAV vector used, and clear it next time. Some groups such as Selecta Biosciences are working on ways to enable repeat dosing, but this is still a work in progress.
Today's paper is, I think, one of the first more formal reports from the Bioviva / Integrated Health Systems collective. A small number of Alzheimer's patients underwent localized delivery of an AAV gene therapy to the brain, upregulating telomerase and klotho. The paper is light on details regarding specifics of the treatment, and there was no control group. I am told via other channels that trial costs were sponsored by a non-profit, and that the patients are representative of the general Alzheimer's population. Still, all that can really be determined from the outcome is that there were no meaningful side-effects. One can compare the patient's cognitive performance with the age-matched Alzheimer's population as a whole, and see that it is better, but the study size is small, and people who have the will, connections, and support to get into a trial of this nature are likely obtaining significantly better care than the average patient.
It is worth noting that a few other companies are developing treatments based on klotho upregulation or telomerase gene therapies within the established regulatory system. There is evidence from animal studies for both approaches to be beneficial in a range of age-related conditions. These are not unreasonable approaches to compensatory therapies that may help patients with neurodegenerative conditions, albeit without addressing the underlying causes of neurodegeneration, and thus having a necessarily limited upside.
Five patients participated in the study and were classified as having mild or moderate dementia. All patients performed witnessed informed consent and provided information from their primary doctor including diagnosis, brain images, and bloodwork. All accepted to participate in genetic testing and telomere testing. Pre-treatment Folstein cognitive testing was performed on all patients and repeated post treatment at intervals of approximately once a month following the initial treatment. Pre-treatment medical laboratory blood analysis was performed and repeated post treatment along with doctor office visits at 3, 6-, 9-, and 12-month periods. Pre-treatment brain Magnetic Resonance Imaging (MRI) was performed and repeated 10 months post treatment.
Recent reports of fatalities in the ASPIRO (AT132) trial highlighted the potential dangers of AAV therapy regarding dose limitations and immunological issues. In the AT132 trial, large doses (1E14 vg/kg or higher) of AAV administered via an intravenous route in patients with preexisting hepatic disease resulted in the death of 4 participants. Mechanisms felt to be causal in these deaths are direct hepatic toxicity from the large viral load as well as stimulation of an aggressive immune response.
Regional AAV gene transfer therapy is felt to be less risky due to the lower does utilized or required, minimal viral load to the liver, and that the regional therapy is often delivered to immune privileged areas like the ocular globes or the central nervous system. The patients in this study received the equivalent of 1/10000 of the dose of the patients in the AT132 trial. Additionally, in this case the dosing was regional rather than intravenous. This extremely low dose essentially minimized the risk of hepatoxicity to almost zero. Additionally, the regional delivery to the CNS minimized the risk of a significant humoral response thereby maximizing the potential for cell transduction.
No short term or long term clinical of laboratory complications were observed or identified. Monitored serum chemistry, electrolyte, and hematological values remained stable throughout the follow-up time. No serious adverse effects such as a visible or laboratory detected innate or humoral immune response was observed or reported. Hepatic function as monitored by clinical laboratory values remained within normal parameters without evidence of hepatic insult. The treatment was well tolerated with only brief minimal physical discomfort at the injection site.
Pretreatment brain MRI compared to post treatment Brain MRI demonstrated no significant changes. Our telomere analysis before and after treatment demonstrated evidence of increased telomerase function. The median and the short telomeres were measurably elongated. Reduced biological age was seen in 4 of 5 participants. Cognitive assessment before and serial cognitive testing after treatment demonstrated a rapid improvement in cognitive function during the first 3.5 months after which the improvement slowed until it leveled off at five months. Thereafter there is a slight decrease slope in the average test score with an average drop of 0.07 points per month. Given that Patients with Alzheimer's dementia typically show an annual decline of 3 points on the on the Folstein test, our results indicate that the AAV hTert and Klotho gene transfer therapy was successful, and the effects of that gene therapy reversed some of the dementia pathology.