For most genetic disorders, treatment is difficult. However, for a few genetic disorders, there are specific treatments because of their clear pathogenesis, such as for a certain type of glutaric aciduria, supplementation of riboflavin in the body can lead to complete remission of the condition. The ideal treatment for all genetic diseases is to change the patient’s genes, i.e. gene therapy, but gene therapy requires a long and costly journey from basic to clinical. Even after spending money, it is not always possible to have good results. Therefore, state support for gene therapy is not strong, especially for Kennedy’s disease, which is an orphan disease due to its extremely low incidence, so it is difficult to get state support. The good thing is that, compared to most genetic diseases, Kennedy’s disease can be said to have some relative treatment strategies because its mechanism is more clearly defined. The cause of Kennedy disease is due to a mutation in the androgen receptor (AR) gene, resulting in its binding to androgen (testosterone) and its displacement from the cytoplasm into the nucleus, which can perform some physiological functions but ultimately cannot be cleared by the nucleus, which can be seen under electron microscopy as a large number of inclusion bodies in the nucleus, resulting in toxicity and leading to degenerative apoptosis of neuronal cells. Knowing this, it is not difficult to understand why early supplemental androgen therapy fails. This is because the cause of KD is not androgen deficiency, but the abnormality of AR structure, and the more androgen supplementation, the more it leads to the acceleration of the pathological process. If androgens are suppressed in the body, this pathological process can theoretically be suppressed, thus slowing down the progression of the disease, which is the mechanism of androgen suppression therapy. Androgen suppression therapy in a broad sense includes drugs (leuprolide) and surgery (debulking), but since surgical debulking is irreversible and there are huge ethical issues, only drug therapy is really available for clinical use. The basic process of drug research is: basic research (cell or animal testing) – clinical research (phase 1) – clinical research (phase 2) – clinical research (phase 3) –Clinical studies (phase 4), which applies to all drugs. Animal studies have shown that leuprolide provides complete remission of clinical symptoms and normalization of life expectancy in KD transgenic rats to a clinical cure level, which is a highly desirable result. Since leuprolide itself has been used in clinical practice for more than 20 years, it is basically safe for internal organs (liver and kidneys), so there is no need to do phase 1 clinical work. Prior to the start of Phase 2, there were several open studies of leuprolide for KD, all of which showed that leuprolide delayed progression in certain areas. The first phase 2 clinical study of leuprolide for KD was published in Ann Neurol in 2009. The results showed that leuprolide significantly improved pathological abnormalities (intranuclear inclusion bodies) in patients with KD, with significant differences in swallowing function and clinical scores in the leuprolide group compared to the control group. 2010 saw the publication of a phase 3 clinical study (JASMITT) in the prestigious Lacet Neurol, which had a larger sample size and used only a barium meal test. to evaluate the effect of leuprolide on swallowing function in patients with KD. The results showed that overall, after 1 year of treatment, there was no difference between the two groups, but there was a trend toward improvement in the leuprolide group, and subgroup analysis showed that for those patients with short duration of disease and early diagnosis, significant improvement in swallowing function was achieved compared to the control group. To date, leuprolide remains the most well-documented and clinically well-studied drug for KD. The available data suggest that leuprolide is very effective in animal studies, but not as effective as in human studies, but there is still evidence of delayed progression, and the earlier the drug is administered, the better the results. Personally, I think the reasons for these phenomena are: 1. the internal environment of humans and animals is different; 2. the absolute period of animal research and human research is generally 1 year, but the relative period of human is much shorter; 3. the human body has a strong compensatory capacity, when clinical symptoms such as weakness, generally 30-50% of motor neurons have degenerated and apoptosis, and if the final diagnosis is confirmed after a transfer to a doctor, in fact The proportion of degenerated neurons is often as high as 80%, and motor neurons cannot be regenerated, and drugs can only protect the undegenerated neurons, which is why the earlier the drug is used, the better the effect. 4. Although the results of the phase 3 clinical are not ideal, the evaluation index is too single, and only the barium meal test is used to evaluate the patient’s swallowing function, and there is no evaluation for limb function. While the early stage of KD mainly involves the function of the proximal limb, swallowing is only affected in the late stage, so it is difficult to fully reflect the overall efficacy of leuprolide in terms of experimental design. Of course, leuprolide itself has major side effects, manifested in the early stage as menopausal syndrome, where patients may experience discomfort such as anxiety, hot flashes, tinnitus, night sweats, etc. The long-term negative effects are mainly on fertility and sexual function, and this drug is more expensive. However, all the above-mentioned adverse effects can disappear after discontinuation of the drug and are reversible. Recently, there was an open study in Neurology on a small sample of clenbuterol for KD, which seems to show that clenbuterol improves motor function in KD patients. This is the only clinical study of a drug other than leucovorin regarding KD. Clenbuterol is a beta2 agonist that selectively relaxes bronchial smooth muscle and is used in the treatment of asthma. Clenbuterol, on the other hand, is commonly known as “lean protein”, which increases protein synthesis and improves lean muscle mass in animals. Studies have shown that the use of 0.04 mg of clenbuterol per day. It improved 6-minute walking ability by about 12% at 3 and 12 months, but did not improve muscle strength and ALS-FRS scores, and also led to a significant increase in blood levels of muscle enzymes. Personally, I think this study has several problems: 1. open design; 2. it only forcibly increases muscle synthesis and does not address the etiology of KD, i.e., damage to motor nerve cells that innervate muscles; 3. the 6-minute walk test is more influenced by subjective factors such as emotion and is less objective than muscle strength scores and scale scores; 4. the degree of improvement in the 6-minute walk test at 3 months is similar to the degree of improvement at 12 months The improvement in the 6-minute walk test at 3 months was similar to the improvement at 12 months, indicating that the improvement stalled after a certain point; 5. The muscle strength and motor function ratings did not improve; 6. The increase in CK indicates an increase in muscle destruction. Theoretically, this drug should have the effect of increasing muscle strength and improving muscle atrophy in all patients with myasthenia gravis and myasthenia gravis, but there is insufficient evidence to confirm that it can slow down the progression of the disease. For these reasons, I personally believe that a more scientific and larger randomized double-blind controlled study is needed. Since this study is not a phase 2 or phase 3 clinical study, patients are not advised to self-administer clenbuterol. Clinical studies on curcumin derivatives are ongoing and the results have not yet been published. For KD, there is another therapeutic target, and heat shock protein. This is because in the absence of androgens, AR forms a stable binding with heat shock proteins in the cytoplasm, and when androgens enter the cell, AR separates from heat shock proteins and binds to androgens and is displaced into the nucleus. If we make the AR bind more firmly to the heat shock protein, the pathological process of KD can be stopped, and the research about this is in the basic stage.