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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2–5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients’ benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1*G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1*G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

In his article “Examining Provisions Related to Consent in the Revised Common Rule,” Dr. Jeremy Sugarman discusses the new informed consent provisions in the revised Common Rule. Dr. Sugarman is ri...

Peptides are more and more considered for the development of drug candidates. However, they frequently exhibit severe disadvantages such as instability and unfavourable pharmacokinetic properties. Many peptides are rapidly cleared from the organism and oral bioavailabilities as well as in vivo half-lives often remain low. In contrast, some peptides consisting solely of d-enantiomeric amino acid residues were shown to combine promising therapeutic properties with high proteolytic stability and enhanced pharmacokinetic parameters. Recently, we have shown that D3 and RD2 have highly advantageous pharmacokinetic properties. Especially D3 has already proven promising properties suitable for treatment of Alzheimer's disease. Here, we analyse the pharmacokinetic profiles of D3D3 and RD2D3, which are head-to-tail tandem d-peptides built of D3 and its derivative RD2. Both D3D3 and RD2D3 show proteolytic stability in mouse plasma and organ homogenates for at least 24h and in murine and human liver microsomes for 4h. Notwithstanding their high affinity to plasma proteins, both peptides are taken up into the brain following i.v. as well as i.p. administration. Although both peptides contain identical d-amino acid residues, they are arranged in a different sequence order and the peptides show differences in pharmacokinetic properties. After i.p. administration RD2D3 exhibits lower plasma clearance and higher bioavailability than D3D3. We therefore concluded that the amino acid sequence of RD2 leads to more favourable pharmacokinetic properties within the tandem peptide, which underlines the importance of particular sequence motifs, even in short peptides, for the design of further therapeutic d-peptides.

It has been shown that amyloid β (Aβ) oligomers play an important role in the pathology of Alzheimer’s disease (AD). D3, a peptide consisting solely of d-enantiomeric amino acid residues, was developed to specifically eliminate Aβ oligomers and is therapeutically active in transgenic AD mice. d-peptides have several advantages over l-peptides, but little is known about their pharmacokinetic potential in vivo. Here, we analysed the pharmacokinetic properties of RD2, a rationally designed and potent D3 derivative. The pharmacokinetic analysis was performed using 3H-RD2 after administration via several routes in mice. The time dependent amount of radiolabelled RD2 was measured in plasma and several organ homogenates by liquid scintillation counting. Furthermore, binding to plasma proteins was estimated. RD2 penetrates into the brain, where it is thought to implement its therapeutic function. All administration routes result in a maximal brain concentration per dose (Cmax/D) of 0.06 (μg/g)/(mg/kg) with brain/plasma ratios ranging between 0.7 and 1.0. RD2 shows a small elimination constant and a long terminal half-life in plasma of more than 2 days. It also exhibits high bioavailability after i.p., s.c. or p.o. administration. These excellent pharmacokinetic properties confirm that RD2 is a very promising drug candidate for AD.