KD chinese technical group of the draft
In November, 2023
1. Androgen blockade, how AR antagonists are used in the treatment of SBMA.
With the increasing research on the molecular mechanism of SBMA pathogenesis, Androgen-dependent blockade, prevention of androgen receptor and androgen binding has become the main direction of research therapeutic agents, So androgen-blocking drugs (ADT) - -leuprorelin (mainly approved in Japan), Dutasteride (mainly North America), etc., And AR antagonists considered as effective means to potentially inhibit the toxicity of AR-POLYQ polymers, Drugs such as ARV-766 have been developed and entered clinical trials, So do these drugs really work, The author believes that the key is to understand the gain of function (GOF) and loss of normal function (LOF) of the toxic protein inhibition produced after the combination of androgen and AR.
The expanded AR of polyQ abnormally enhances its own expression in SBMA skeletal muscle, motor neurons, and reducing these overexpressed comodulators is a strategy to inhibit or mitigate AR toxic GOF. SBMA is an X-linked disease that develops in males and is characterized by symptoms associated with toxic GOF and LOF mechanisms, which limits clinical approaches to inhibiting disease proteins. This is particularly relevant to chronic, slowly progressive diseases such as SBMA, which require long-term treatment for three reasons: (i) any treatment is more likely to work before puberty onset, accompanying, or symptom onset, (ii) any treatment that suppresses mutant AR enhances AR LOF, which cannot be ignored in X-related diseases affecting men, and (iii) SBMA patients show signs of androgen insensitivity syndrome, so lifelong treatment must be taken into account. Strengthening AR LOF by medication may exacerbate sexual dysfunction, metabolic syndrome and diabetes, depression and muscle atrophy.
So how to scientifically use drugs to control the progress of SBMA in this direction? Given that there are currently no other effective agents for controlling SBMA development, It is suggested that on the basis of monitoring CK, testosterone hormone levels, To control the nongrowth of CK (if too high, Such as continuing by 5-10 times above the normal limit), Testosterone levels depending on age (reproductive age, Middle age to preserving partial sexual function), It is advisable to maintain around the lower limit of the normal level (whether the morning boom can occur as a daily monitoring method), Medication should be considered to delay muscle atrophy progression, In terms of drug selection, the author believes that the second generation AR antagonists have more benefits to patients than ADT drugs (patients have taken Enzalutamide, CK dropped from 2600 to 1000 in a month, Physical sensation is enhanced, Specific to wait for an expert to confirm!), Since only inhibiting AR, the effect on androgen levels is indirectly relatively small, but produces the effect of AR variants.
As for the newer AR-PROTAC drugs, the results of AR component monitoring in patients have not been seen in relevant articles, and further study on drug LOF is needed.
2.About clenbuterol treatment for SBMA
Italian scientists conducted two studies of the efficacy and tolerance of clenbuterol treatment in SBMA (in SBMA mice and patients, respectively) to analyze the effects of β -agonist stimulation on skeletal muscle myotube cells in SBMA mice and patients. Found that treatment of myotubes expressing POLYQ-AR with the β -agonist clenbuterol increased their size.clenbuterol activates the phosphatidylinositol-3-kinase (PI3K) / Akt / rapamycin mechanism target (mTOR) pathway to reduce the accumulation of polyq AR. Treatment of SBMA knock-in mice with clenbuterol initiated at the onset of the disease had improved motor function and prolonged survival.clenbuterol ameliorated muscle pathology, attenuated altered glycolytic-oxidative metabolism and induced hypertrophy of glycolytic and oxidative fibers in SBMA muscle. These results suggest that β -agonist stimulation is a novel therapeutic strategy for SBMA.
In addition, the trial observed an increase in serum CK during clenbuterol treatment. Although elevated CK has been reported during β -agonist treatment in both animals and humans, SBMA patients usually have high CK levels and present with myopathic abnormalities by muscle biopsy, including massive induction of AR-POLYQ with a central nucleus. Subsequent studies found that these fibers collapsed upon β -agonist-induced stimulation, resulting in increased CK release. More severe muscle damage seems unlikely because of the long-term motor performance of the test subjects.
During the trial, the patient did not have the routine side effects of clenbuterol in the heart, which indicates the special adaptability of SBMA patients to the drug. It is unclear whether the improvement in 6 MWD observed during clenbuterol administration simply reflects an anabolic effect or whether it may be related to the protective activation of Akt signaling by the drug. Furthermore, a non-specific sympathomimetic effect should also be considered. Italian studies show that clenbuterol has a positive effect on SBMA disease in suppressing the progression of skeletal muscle atrophy.
Thus, clenbuterol could be used as a muscle symptom delaying agent for SBMA.
3. Drug analysis in clinical trials
At present, researchers are deepening the toxicity mechanism of polyQ amplification and loss of function based on "AR", and have opened new clinical trials. Angel Taiwan initiated a Phase 1b / 2a clinical study of AJ 201, a curcumin-based compound designed to activate Nrf 1 and Nrf 2 cellular pathways to promote the degradation of the mutant androgen receptor (AR) protein causing Kennedy disease; NIDO-361 is a new small molecule that binds a unique site AF2 on the androgen receptor and corrects transcriptional dysregulation to restore healthy cellular function. Late last year, the company launched clinical studies of NIDO-361 in humans.
1） the knowledge about AJ 201
AJ 201 is a new chemical entity being developed for the treatment of spinal cord and medulla muscular dystrophy (SBMA). At the molecular level, AJ 201 exerts a variety of cellular effects to activate the nuclear factor RBC 2-related factor 2 (Nrf 2) in response to oxidative damage, Nrf 1 enhances ubiquitin proteasome system (UPS) -mediated degradation, and heat shock factor 1 (Hsf 1) to promote protein folding. In an animal model of SBMA, AJ 201 alleviated behavioral deficits in motor function, ameliorated muscle atrophy, reduced accumulation of mutant AR aggregates in muscle, and activated expression of antioxidant enzymes.
The therapeutic effect of Aj201 also has problems with GOF and LOF. Nrf 1 enhances UPS-mediated degradation and promotes ar-polyq polymers degradation, which means that the toxic protein inhibition function gof is available, but the same question with other AR protein inhibitors is that the lack of AR function protein is inevitable, is there a loof problem, does it mean only inhibition without treatment? The therapeutic effect of Aj201 should be to increase the level of heat shock protein hsp and make it not easy to break ar, but is it still useful not to break ar? Only nrf 2 increased the expression of intracellular antioxidant enzymes, and this protective effect is unique to it.
2）NIDO-361 solved the GOF and LOF problems
NIDO drug developers showed that AF2 modulators do not affect normal AR signaling function but promote corepressor binding, and to assess the mechanisms by which AF2 modulation attenuates SBMA-related phenotypes, Dr. Paul Taylor's team analyzed the AR activity of polyQ amplification in response to TA and MEPB. Neither TA nor MEPB treatment transduced polyQ amplified AR protein in stable or stably transfected motor neurons (MN 1) cells or transiently transfected HEK293T cells, suggesting that the reduction in SBMA-related toxicity due to TA and MEPB treatment is not solely due to enhanced AR degradation. In response to treatment of TA and MEPB, the presence of high molecular weight, multimeric ar complexes and aggregates was not altered. Consistent with these observations, MEPB treatment did not statistically significantly alter the expression levels of endogenous mouse AR or transgenic human AR in the muscle and spinal cord of AR121Q mice, and neither MEPB nor TA treatment altered transgenic AR expression in Drosophila, suggesting that attenuated TA and MEPB-mediated toxicity occurred independently of AR aggregation. Furthermore, neither MEPB nor TA treatment altered the DHT-dependent nuclear transposition of the polyQ-amplified ar in HEK293T cells and Drosophila (Figure 6a, b). MEPB treatment did not significantly alter the trans-activation ability of AR amplified by polyQ. Finally, eight AR response genes expressed (Igfbp5, Mt2, Sgk 1, Trib 1, Camkk2, Tsc22d3, Plk3r3, and AR) in which were motor neurons were selected and the effect of MEPB responses to ligand-dependent changes in transcription of MN 1 cells (MN 1-AR24Q cells) stably expressing human AR was assessed. Statistically significant ligand-dependent changes in transcription for seven of the eight target genes were confirmed, but no effect on MEPB was found.
The results of these tests suggest that although AR signaling remains intact, modulation of AF2 by SARMs selectively alters AR activity and reduces the toxicity associated with polyQ-expanded AR, but other aspects of the AR response remain intact. Indeed, the reversal of testicular atrophy in SBMA mice after treatment with MEPB is consistent with this conclusion.
This means that NIDO361 is ideal for the true treatment of SBMA, resolving the contradiction between GOF and LOF.
4. The start point of treatment in SBMA patients should be advanced to puberty.
Taken together, it is clear that SBMA affects a wide range of cell types and tissues, and while motor neuron degeneration and neuromuscular destruction are considered hallmarks of the disease, a broader view of the pathogenesis of SBMA may bring new therapeutic opportunities and mechanistic insights.
SBMA onset time has been clear foreign research since puberty, patients group communication to the earliest 23 patients (2006, CK value 1780), SBMA patients since the puberty pathogenic AR gene start disease, should start early SBMA patients treatment and prevention, specific should prepare related diagnosis and treatment strategy research.
The level of androgen secretion in SBMA patients is the highest in the lifetime, and the cellular concentration of androgen is the key to AR dissociating HSP molecules into the nucleus to open AR gene transcription and amplify polyQ. At this time, the focus should be placed on ensuring the normal development of muscle and nerve in SBMA patients! At the same time, timely control of the pathogenic mechanism to play a role, the adverse impact in the minimum, this is the most ideal scheme.
The above is the patient's point of view, please criticize and correct the experts!