Future Perspectives of Prime Editing for the Treatment of Inherited Retinal Diseases

Inherited retinal diseases (IRD) are a clinically and genetically heterogenous group of diseases and a leading cause of blindness in the working-age population. Even though gene augmentation therapies have shown promising results, they are only feasible to treat a small number of autosomal recessive IRDs, because the size of the gene is limited by the vector used. DNA editing however could potentially correct errors regardless of the overall size of the gene and might also be used to correct dominant mutations. Prime editing is a novel CRISPR/Cas9 based gene editing tool that enables precise correction of point mutations, insertions, and deletions without causing double strand DNA breaks. Due to its versatility and precision this technology may be a potential treatment option for virtually all genetic causes of IRD. Since its initial description, the prime editing technology has been further improved, resulting in higher efficacy and a larger target scope. Additionally, progress has been achieved concerning the size-related delivery issue of the prime editor components. This review aims to give an overview of these recent advancements and discusses prime editing as a potential treatment for IRDs

Future Perspectives of Prime Editing for the Treatment of Inherited Retinal Diseases

Inherited retinal diseases (IRD) are a clinically and genetically heterogenous group of diseases and a leading cause of blindness in the working-age population. Even though gene augmentation therapies have shown promising results, they are only feasible to treat a small number of autosomal recessive IRDs, because the size of the gene is limited by the vector used. DNA editing however could potentially correct errors regardless of the overall size of the gene and might also be used to correct dominant mutations. Prime editing is a novel CRISPR/Cas9 based gene editing tool that enables precise correction of point mutations, insertions, and deletions without causing double strand DNA breaks. Due to its versatility and precision this technology may be a potential treatment option for virtually all genetic causes of IRD. Since its initial description, the prime editing technology has been further improved, resulting in higher efficacy and a larger target scope. Additionally, progress has been achieved concerning the size-related delivery issue of the prime editor components. This review aims to give an overview of these recent advancements and discusses prime editing as a potential treatment for IRDs

Akuter Stress und kardiale interozeptive Genauigkeit in einer Herzschlagzählaufgabe

Interozeption, d.h. die Wahrnehmung und Verarbeitung körperinnerer Signale, hängt mit der Aktivität eines Körperorgans (z.B. kardiale Aktivierung) zusammen. Die Organaktivität wird maßgeblich durch Stress beeinflusst, der beispielsweise durch soziale Situationen oder Schmerz ausgelöst wird. Auch wenn erste Erkenntnisse implizieren, dass Stress die bewusste Ebene der Interozeption („interozeptive Genauigkeit“/IG) beeinflussen könnte, sind der Zeitverlauf dieses Effekts und die Rolle von Organaktivierung bislang unklar. Anhand eines Gruppenexperiments mit gesunden Versuchspersonen (je n=33 Stress- und Kontrollgruppe, w=48) wurde die Auswirkung von akutem Stress (sozial-evozierter Kaltwassertest) auf IG in einer Herzschlagzählaufgabe zu vier unterschiedlichen Zeitpunkten (pre-Stress/post-Stress-1/2/3) untersucht. Der Stressor führte zu einem Anstieg von selbstberichtetem Stress (sowie Speichelcortisol). Die Herzrate (Organaktivität) sowie die IG blieben jedoch, entgegen der Erwartungen, sowohl zwischen den Gruppen als auch über die Zeit, unverändert. Unabhängig von der Bedingung und den Zeitpunkten zeigte sich außerdem eine Tendenz, die tatsächlichen Herzschläge zu 56% zu unterschätzen. Bei konstanter Herzrate (M=81.5 bpm) über alle Versuchsbedingungen hinweg konnten die gezählten Herzschläge alleine (M=28.55) somit die IG (M=.43) vorhersagen (r=.962, p<.001). Diese Ergebnisse legen nahe, dass sowohl die zentrale Rolle der gezählten Herzschläge auf die IG, als auch jene Organaktivierung, die durch akuten Stress verändert wird und sich in einer Veränderung der gezählten Herzschläge widerspiegelt, bei Anwendung der Herzschlagzählaufgabe, berücksichtigt werden muss

Cardiac interoceptive accuracy is not altered by acute stress

peer reviewedInteroception is the sense to process and perceive inner bodily processes (e.g., organ activity). Stress affects and possibly alters interoceptive signal processing. For example, acute stress stimulates the cardiovascular system, thereby increasing organ activity, which may ultimately feed into enhanced cardiac perception, indicated by the ability to count one's own heartbeats (i.e., interoceptive accuracy/IAcc). Furthermore, cortisol release may also affect the processing of cardiac signals at cortical level. Hence, we hypothesized that an acute stressor enhances cardiac IAcc, dependent on augmented sympathetic activation (i.e., heart rate), and cortisol release. We investigated cardiac IAcc in a heartbeat counting task (HCT) before and after (0, 20, 40 min.) a stress test (SECPT vs. control; n=33 each). IAcc and heart rate (HR) were neither effected by stress, nor changed over time. In addition, the number of counted heartbeats did not change, although participants were significantly stressed (self-report and salivary cortisol). We also found a tendency of underreporting heartbeats by 56% independent of group and time. Furthermore, the given constant heart rate (M=81.5 bpm)was positively correlated with IAcc (M=.43) independent of all conditions (r=.962, p<.001). IAcc in the HCT is determined by changes in organ activity (i.e., HR), but not by cortisol. As the SECPT did not change HR, the SECPT and/or the HCT may have limited suitability for investigating acute stress effects on cardiac interoception

Lomre (Microstomus kitt W), en kandidat for oppdrett? -En pilotstudie med fokus på yngelproduskjon

-Prosjektet hadde til hensikt å undersøke potensialet for intensivt oppdrett av lomre. Hovedfokus var på produksjon av yngel. Stamfisk ble fanget med garn utenfor Senja, og transportert til Havbruksstasjonen i Tromsø. Det var noe dødelighet forbundet med fangst og transport, men hovedandelen av fisken tålte behandlingen godt, og begynte etter kort tid å ta til seg fôr. Egg og sperm ble samlet ved stryking i perioden fra slutten av mai til begynnelsen av juni. Befruktningsraten var nær 90%. Eggene klekket gjennomsnittlig ved 117 døgngrader etter befruktning, og den gjennomsnittlige dødeligheten under inkubasjonsperioden var på 26 %. Det ble ikke observert forhøyet dødelighet hos stamfisken etter stryking, noe som forsterker inntrykket av at lomren er en robust fisk som tåler håndtering. I fasen fra klekking til metamorfose (startfôringsperioden) ble tre ulike produksjonsprotokoller testet ut. Protokollene varierte med hensyn på vannmiljø, lysmiljø og fôringsregime. I protokoll 1 ble det brukt kontinuerlig lys som varierte mellom 2400 og 2800 lux. I protokoll 2 og 3 ble brukt kontinuerlig lys som varierte mellom 250 og 300 lux. I protokoll 1 ble det brukt vannflow på 0.6 L/min, og et filter på 350m ved utløpet av karet. I protokoll 2 ble vannflowen økt til 0.8-0.9 L/min mens filteret var uforandret. I protokoll 3 var vannflowen den somme som i protokoll 2 mens filteret ved utløpet var grovere (500 m). Filtrert sjøvann med in situ temperatur ble brukt i alle protokoller, og temperaturen varierte mellom 7.5 og 11.7 ºC. Protokoll 3 skilte seg fra protokoll 1 og 2 med en betydelig lavere dødelighet. Vi tror at forskjellene i fôringsregime var den viktigste årsaken til de observerte forskjeller i dødelighet. I protokoll 3 ble larvene fôret med en kombinasjon av Artemia og tørrfôr fra dag 30, mens larvene i protokoll 1 og 2 fikk bare Artemia i samme periode