Background
There are currently no FDA-approved pharmaceutical treatments for mild cognitive impairment (MCI), nor for MCI with associated anxiety. Importantly, these two disorders often go hand in hand (Orgeta et al, 2022). As the elderly population increases among developed nations, MCI and anxiety already affect 10% - 15% of those 65 and older, and because MCI is often a transitional stage into the more serious diagnosis of dementia (Anderson 2019), there is a demand for new and more effective therapies.
Many drugs that are currently used to treat chronic anxiety and depression were approved in the late 1980s. This includes selective serotonin reuptake inhibitors (SSRIs, like Zoloft) and similar approaches based on norepinephrine (SNRI's, like Cymbalta). These drugs have proven to be useful treatments for some patients, but besides continuing concerns about a wide range of serious side effects (largely attributed to the systemic delivery of the drug, which affects 15 subtypes of serotonin), they are not intended to improve memory, and in some cases may exacerbate memory problems (Anagha et al, 2021). Meanwhile, drugs like Donepezil (brand name Aricept) which are used to treat dementia, are not intended as anxiolytics, and may likewise result in paradoxical adverse reactions (Hakimi et al, 2020).
In search of more effective treatments to manage chronic anxiety, depression, and cognitive decline, including MCI, there has been a resurgence of interest in the use of serotonergic hallucinogenic compounds (i.e., psychedelics, like psilocybin), which act as serotonin 2A receptor (5-HT2AR) agonists (Garcia-Romeu et al, 2022). Clinical studies with these compounds continue to show promising efficacy, but their hallucinogenic properties, which may play an important therapeutic role (Raj et al, 2023; van den Berg et al, 2022), will probably limit their widespread acceptance. This has led to the development of psychedelic analogs, such as molecules similar to LSD that are said to not produce hallucinations (Lewis et al, 2023). Whether such approaches will prove to be therapeutically efficacious and safe remains to be seen.
A novel approach
Given the demand to develop an effective treatment for MCI and anxiety, what is desirable is a therapeutic that (1) precisely targets only the 5HT2A receptors in the brain, (2) can be delivered easily and noninvasively directly to the brain, (3) shows superior efficacy in treating MCI and anxiety, (4) lasts many months with each treatment, (5) has no undesirable physiological or behavioral side effects, (6) has no discernable toxicological or safety concerns, and (7) would be cost comparable to existing pharmaceutical treatments.
The Cognigenics solution, described in the associated article in Translational Psychiatry, successfully addresses each of the first six elements in mice and rats, with a similar electrophysiological profile demonstrated in human iPSC neurons in vitro. After discussions with pharmaceutical consultants and genetic reagent manufacturers, we have reason to believe that the seventh desirable element, a relatively low cost, is also achievable due to the large potential patient need.
We first tested our intranasal genetic editing approach using CRISPR-cas9, in mice, to permanently modify the 5HT2A receptor, and we found it to be highly effective in improving memory and reducing anxiety (Rohn et al, 2023). However, we assessed that it would be unlikely, at least at this early phase of the development of neurogenetic therapeutics, that a DNA-based treatment would be approved for a fairly common mental health disorder. This motivated our current work, where we have demonstrated that we can achieve equally effective results, as a temporary treatment, with an RNA edit. Our approach, which relies on the RNA-induced silencing complex (RISC) pathway, allows for an extremely precise form of RNA interference editing. To study the level of precision and help address concerns about the possibility of off-target edits, we searched for potential matches of our editing sequence throughout the entire mouse genome, and found only one -- the intended target that results in silencing production of the 5HT2A receptor. Our method is thus a precise 5HT2A antagonist (and not a broad stroke agonist, like psychedelic compounds), which in standard rodent behavioral tests leads to both a significant reduction in anxiety and a highly significant improvement in memory.
Takeaway message
At this preclinical stage of our R&D, based on our experimental studies we have high confidence that our approach is an effective treatment for MCI and anxiety in mice and rats, with no evidence for off-target, safety, or toxicology concerns. Whether this method will be as effective in humans will require clinical trials, which we are actively working toward achieving. If those trials are successful, then RNA editing may help to create a new class of highly efficacious and precision therapeutics for a broad range of psychiatric disorders, beginning with MCI and anxiety.
References
Anagha K, Shihabudheen P, Uvais NA. Side Effect Profiles of Selective Serotonin Reuptake Inhibitors: A Cross-Sectional Study in a Naturalistic Setting. Prim Care Companion CNS Disord. 2021 Jul 29;23(4):20m02747. doi: 10.4088/PCC.20m02747. PMID: 34324797.
Anderson ND. State of the science on mild cognitive impairment (MCI). CNS Spectr. 2019 Feb;24(1):78-87. doi: 10.1017/S1092852918001347. Epub 2019 Jan 17. PMID: 30651152.
Garcia-Romeu A, Darcy S, Jackson H, White T, Rosenberg P. Psychedelics as Novel Therapeutics in Alzheimer's Disease: Rationale and Potential Mechanisms. Curr Top Behav Neurosci. 2022;56:287-317. doi: 10.1007/7854_2021_267. PMID: 34734390.
Hakimi Y, Petitpain N, Pinzani V, Montastruc JL, Bagheri H. Paradoxical adverse drug reactions: descriptive analysis of French reports. Eur J Clin Pharmacol. 2020 Aug;76(8):1169-1174. doi: 10.1007/s00228-020-02892-2. Epub 2020 May 16. PMID: 32418024.
Lewis V, Bonniwell EM, Lanham JK, Ghaffari A, Sheshbaradaran H, Cao AB, Calkins MM, Bautista-Carro MA, Arsenault E, Telfer A, Taghavi-Abkuh FF, Malcolm NJ, El Sayegh F, Abizaid A, Schmid Y, Morton K, Halberstadt AL, Aguilar-Valles A, McCorvy JD. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Rep. 2023 Mar 28;42(3):112203. doi: 10.1016/j.celrep.2023.112203. Epub 2023 Mar 6. PMID: 36884348; PMCID: PMC10112881.
Orgeta V, Leung P, Del-Pino-Casado R, Qazi A, Orrell M, Spector AE, Methley AM. Psychological treatments for depression and anxiety in dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2022 Apr 25;4(4):CD009125. doi: 10.1002/14651858.CD009125.pub3. PMID: 35466396; PMCID: PMC9035877.
Raj P, Rauniyar S, Sapkale B. Psychedelic Drugs or Hallucinogens: Exploring Their Medicinal Potential. Cureus. 2023 Nov 13;15(11):e48719. doi: 10.7759/cureus.48719. PMID: 38094517; PMCID: PMC10716812.
Rohn TT, Radin D, Brandmeyer T, Linder BJ, Andriambeloson E, Wagner S, Kehler J, Vasileva A, Wang H, Mee JL, Fallon JH. Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice. PNAS Nexus. 2023 Jun 20;2(6):pgad170. doi: 10.1093/pnasnexus/pgad170. PMID: 37346271; PMCID: PMC10281383.
van den Berg M, Magaraggia I, Schreiber R, Hillhouse TM, Porter JH. How to account for hallucinations in the interpretation of the antidepressant effects of psychedelics: a translational framework. Psychopharmacology (Berl). 2022 Jun;239(6):1853-1879. doi: 10.1007/s00213-022-06106-8. Epub 2022 Mar 29. PMID: 35348806; PMCID: PMC9166823.