Nucleic Acid Therapy Abstracts 1

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The use of nucleic acid in aged patients with memory impairment.
            (Cameron, 1958) Download
In the last year we have been exploring the use of RNA, orally in capsules, the maximum amount being 75, gms daily. The average amount is considerably lower, ranging from 0 to 20 gms. In all 23 patients favorable results were noted. In 50% the results were good. The best results were obtained from patients having severe memory deficits and marked confusion. In most of these the confusion cleared up, orientation returned and there was considerable or complete restoration of retention.

Effects Of Ribonucleic Acid On Memory Defect In The Aged.
            (Cameron et al., 1963) Download
The purpose of the present investigation is to discover at what points in the memorial process ribonucleic acid is operative. We have shown again and with a larger group of patients the effects of RNA administered intravenously upon the memory performance of patients suffering from organic memory defect.

Nucleic Acid-Based Theranostics for Tackling Alzheimer's Disease.
            (Chakravarthy et al., 2017) Download
Nucleic acid-based technologies have received significant interest in recent years as novel theranostic strategies for various diseases. The approval by the United States Food and Drug Administration (FDA) of Nusinersen, an antisense oligonucleotide drug, for the treatment of spinal muscular dystrophy highlights the potential of nucleic acids to treat neurological diseases, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disease characterized by progressive impairment of cognitive function and behavior. It is the most common form of dementia; it affects more than 20% of people over 65 years of age and leads to death 7-15 years after diagnosis. Intervention with novel agents addressing the underlying molecular causes is critical. Here we provide a comprehensive review on recent developments in nucleic acid-based theranostic strategies to diagnose and treat AD.


 

Nucleic Acid-Based Therapeutics for Pulmonary Diseases.
            (Chen et al., 2018)  Download
Nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. The susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. To overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. However, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. Therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. In this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. The latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed.

RNA and memory: a re-evaluation of present data.
            (Enesco, 1967) Download
Studies on the beneficial effects of yeast RNA treatment on learning and memory in senile patients and in animal experimentation are reviewed in this paper. Experimental evidence is cited showing that yeast RNA is not incorporated into brain tissue and does not increase brain synthetic activity. Thus the therapeutic effects of RNA treatment cannot be explained in direct relation to the hypothesis that RNA within the brain encodes memory information. Evidence for stimulant action of RNA, mediated by uric acid, its primary metabolite, is presented as the basis for an alternative theory which would explain RNA action in pharmacological terms.

Interanimal "memory" transfer: results from brain and liver homogenates.
            (Frank et al., 1970) Download
Sixty mice received either shock or no shock in a shuttle box, or nonspecific stress in another apparatus. Brain and liver homogenates from these animals were then injected into 120 naive recipients, who were all tested in the shuttle box. Subjects receiving brain or liver from shocked or stressed donors had significantly higher latencies than control counterparts. These results are interpreted in terms of stress, rather than a memory transfer hypothesis.


 

Therapeutic applications of nucleic acids and their analogues in Toll-like receptor signaling.
            (Gosu et al., 2012) Download
Toll-like receptors (TLRs) belong to a family of innate immune receptors that detect and clear invading microbial pathogens. Specifically intracellular TLRs such as TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids such as double-stranded RNA, single-stranded RNA and CpG DNA respectively derived from microbial components. Upon infection, nucleic acid sensing TLRs signal within endosomal compartment triggering the induction of essential proinflammatory cytokines and type I interferons to initiate innate immune responses thereby leading to a critical role in the development of adaptive immune responses. Thus, stimulation of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, allergies, malignant neoplasms and autoimmunity. This review summarizes the therapeutic applications of nucleic acids or nucleic acid analogues through the modulation of TLR signaling pathways.

Nucleic Acid-Based Therapeutics Relevant to Neuroimmune Conditions.
            (Greenfield and Hauser, 2019)  Download
Treatments for autoimmune neurologic disease have become increasingly powerful, yet have not been able to eliminate disease activity altogether. Underlying neurodegeneration may start early on in the course of neuroimmune diseases such as multiple sclerosis (MS), making early aggressive treatment of immunologic reservoirs an increasingly recognized treatment strategy. There is a need for more specific therapeutic targets as well. Novel approaches to treating these conditions, from cell-based therapies to gene therapy, show promise for filling these unmet needs (Table ​(Table1).1). Nucleic acid-based therapies have the potential to more precisely target specific populations of target cells and more precisely correct specific gene regulatory abnormalities, avoiding wider-scale immunosuppression and off-target effects.

Nucleic acid therapy for lifespan prolongation: present and future.
            (Lai, 2011) Download
Lifespan prolongation is a common desire of the human race. With advances in biotechnology, the mechanism of aging has been gradually unraveled, laying the theoretical basis of nucleic acid therapy for lifespan prolongation. Regretfully, clinically applicable interventions do not exist without the efforts of converting theory into action, and it is the latter that has been far from adequately addressed at the moment. This was demonstrated by a database search on PubMed and Web of Science, from which only seven studies published between 2000 and 2010 were found to directly touch on the development of nucleic acid therapy for anti-aging and/or longevity enhancing purposes. In light of this, the objective of this article is to overview the current understanding of the intimate association between genes and longevity, and to bring the prospect of nucleic acid therapy for lifespan prolongation to light.


 

Effect of nucleic acid supplements in the diet on rate of regeneration of liver in rats.
            (Newman and Grossman, 1951) Download
In partially hepatectomized rats, the rate of liver regeneration was significantly accelerated by adding ribonucleic or desoxyribonucleic acid to the diet. The addition to the diet of tissues rich in nucleic acids, spleen and kidney, was also effective in speeding liver regeneration.

On the influence of nucleic acids of various origin upon the growth and longevity of the white mouse
            (Robertson, 1928) Download
In 1922 it had begun to appear probable to the author that the course of frrowth and the onset of senescence in animals and plants are determined by the ratio of nuclear (chromosomal) materials to the cytoplasm (protein) of the cells composing the organism (the nucleo-cytoplasmic ratio). This conception has been elaborated in other publications (6, 7), and need not further detain us here. It is sufficient to state that, guided by this conception, it appeared possible that if the nuclei in animal tissues could be supplied with nutritive …

Therapeutic potential of RNAi in metabolic diseases.
            (Rondinone, 2006)  Download
Over the past years RNA interference (RNAi) has exploded as a new approach to manipulate gene expression in mammalian systems. More recently, RNAi has acquired interest as a potential therapeutic strategy. This review focuses on the potential therapeutic use of RNAi for metabolic diseases, the current understanding of RNAi biology, and how RNAi has been utilized to study the role of different genes in the pathogenesis of diabetes and obesity. Also reviewed are the in vivo proof-of-principle experiments that provide the preclinical justification for the development of RNAi-based therapeutics for diabetes and the key challenges that currently limit its application in the clinical setting.


 

Therapeutic nucleic acids: current clinical status.
            (Sridharan and Gogtay, 2016) Download
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are simple linear polymers that have been the subject of considerable research in the last two decades and have now moved into the realm of being stand-alone therapeutic agents. Much of this has stemmed from the appreciation that they carry out myriad functions that go beyond mere storage of genetic information and protein synthesis. Therapy with nucleic acids either uses unmodified DNA or RNA or closely related compounds. From both a development and regulatory perspective, they fall somewhere between small molecules and biologics. Several of these compounds are in clinical development and many have received regulatory approval for human use. This review addresses therapeutic uses of DNA based on antisense oligonucleotides, DNA aptamers and gene therapy; and therapeutic uses of RNA including micro RNAs, short interfering RNAs, ribozymes, RNA decoys and circular RNAs. With their specificity, functional diversity and limited toxicity, therapeutic nucleic acids hold enormous promise. However, challenges that need to be addressed include targeted delivery, mass production at low cost, sustaining efficacy and minimizing off-target toxicity. Technological developments will hold the key to this and help accelerate drug approvals in the years to come.

RNA “memory pills” and memory: a review of clinical and experimental status
            (Sweet, 1969) Download
Various studies which have investigated the effects of RNA and RNA synthesizers on memory and/or learning were evaluated. It was concluded that findings have thus far failed to lend support to the notion that RNA functions as a memory template or encoder. In the future, public announcements regarding the efficacy of “memory drugs” or “memory pills” should be viewed with constructive skepticism.

Nucleic Acid Therapeutics for Neurological Diseases.
            (Watts et al., 2019)  Download
The development of nucleic acid therapeutics for neurological diseases is rapidly evolving, with nusinersen approved and more than 10 nucleic acid drug candidates in clinical development for use in disorders of the CNS. Dozens more nucleic acid drugs for neurological targets are at the stage of early preclinical development.


 

Changes in the concentration of ribonucleic acid during wound tissue regeneration.
            (Williamson and Guschlbauer, 1961) Download
The metabolism of ribonucleic acid (RNA) in regenerating wound tissue may be expected to be of special importance since the synthesis of protein is one of the principal metabolic activities of this tissue1,2. The relative amount of RNA in this tissue at different stages of regeneration should give some insight into the protein metabolism. A complicating factor is the fact that considerable amounts of two quite different types of protein are formed, the intracellular ‘metabolically-active’ proteins, and collagen.

 


References

Cameron, DE (1958), ‘The use of nucleic acid in aged patients with memory impairment.’, Am J Psychiatry, 114 (10), 943. PubMed: 13508936
Cameron, DE, et al. (1963), ‘Effects Of Ribonucleic Acid On Memory Defect In The Aged.’, Am J Psychiatry, 120 320-25. PubMed: 14069456
Chakravarthy, M, et al. (2017), ‘Nucleic Acid-Based Theranostics for Tackling Alzheimer’s Disease.’, Theranostics, 7 (16), 3933-47. PubMed: 29109789
Chen, J, et al. (2018), ‘Nucleic Acid-Based Therapeutics for Pulmonary Diseases.’, AAPS PharmSciTech, 19 (8), 3670-80. PubMed: 30338490
Enesco, HE (1967), ‘RNA and memory: a re-evaluation of present data.’, Can Psychiatr Assoc J, 12 (1), 29-34. PubMed: 16961014
Frank, B, DG Stein, and J Rosen (1970), ‘Interanimal “memory” transfer: results from brain and liver homogenates.’, Science, 169 (3943), 399-402. PubMed: 5465368
Gosu, V, et al. (2012), ‘Therapeutic applications of nucleic acids and their analogues in Toll-like receptor signaling.’, Molecules, 17 (11), 13503-29. PubMed: 23151919
Greenfield, AL and SL Hauser (2019), ‘Nucleic Acid-Based Therapeutics Relevant to Neuroimmune Conditions.’, Neurotherapeutics, 16 (2), 314-18. PubMed: 31087242
Lai, WF (2011), ‘Nucleic acid therapy for lifespan prolongation: present and future.’, J Biosci, 36 (4), 725-29. PubMed: 21857119
Newman, EA and MI Grossman (1951), ‘Effect of nucleic acid supplements in the diet on rate of regeneration of liver in rats.’, Am J Physiol, 164 (1), 251-53. PubMed: 14810929
Robertson, TB (1928), ‘On the influence of nucleic acids of various origin upon the growth and longevity of the white mouse’, Australian J Exp Biology Med Sci, PubMed:
Rondinone, CM (2006), ‘Therapeutic potential of RNAi in metabolic diseases.’, Biotechniques, Suppl 31-36. PubMed: 16629385
Sridharan, K and NJ Gogtay (2016), ‘Therapeutic nucleic acids: current clinical status.’, Br J Clin Pharmacol, 82 (3), 659-72. PubMed: 27111518
Sweet, RC (1969), ‘RNA “memory pills” and memory: a review of clinical and experimental status’, The Psychological Record, PubMed:
Watts, JK, RH Brown, and A Khvorova (2019), ‘Nucleic Acid Therapeutics for Neurological Diseases.’, Neurotherapeutics, 16 (2), 245-47. PubMed: 31037650
Williamson, MB and W Guschlbauer (1961), ‘Changes in the concentration of ribonucleic acid during wound tissue regeneration.’, Nature, 192 454-55. PubMed: 14007253