BEIJING, China — Significant strides have been made in the treatment of Parkinson’s disease through the development of a gene therapy strategy. This approach developed by Chinese researchers selectively targets the circuitry affected by Parkinson’s disease, effectively reducing core motor symptoms in rodent and nonhuman primate subjects.
Parkinson’s disease, a common neurodegenerative condition predominantly affecting the elderly, is characterized by the loss of dopaminergic neurons in the midbrain. It afflicts over six million individuals worldwide.
According to the Michael J. Fox Foundation, three key symptoms of Parkinson’s include:
- Stiffness (rigidity): muscle stiffness detected by a doctor on examination.
- Slowness (bradykinesia): decrease in spontaneous and voluntary movement; may include slower walking, less arm swinging while walking, or decreased blinking or facial expression.
- Resting tremor: a rhythmic, involuntary shaking that occurs in a finger, hand or limb when it’s relaxed and disappears during voluntary movement.
The disease’s motor symptoms result from imbalances in two types of medium spiny neurons: dopamine receptor D1-expressing neurons (D1-MSN) and D2-expressing neurons (D2-MSN).
D1-MSNs, which make up the direct pathway, promote movement, while D2-MSNs, part of the indirect pathway, mediate movement inhibition. In Parkinson’s disease, dopamine depletion leads to reduced activity in the direct pathway and increased activity in the indirect pathway, causing motor symptoms like bradykinesia (slowness of movement), rigidity, and tremors.
The primary treatment for Parkinson’s disease, levodopa (L-Dopa), helps restore dopamine function but is associated with long-term motor complications. Therefore, researchers sought a more precise and stable approach, according to a media release.
The team from the Chinese Academy of Sciences (CAS) explored the possibility of selectively targeting D1-MSNs, the neurons promoting movement, by introducing neuronal activity-regulating elements. They achieved this by using a highly efficient retrograde adeno-associated virus (AAV) called AAV8R12 to label D1-MSNs and a new promoter, G88P2/3/7, with strong D1-MSN activity. This gene therapy strategy involved introducing a chemogenetic effector called rM3Ds, which matched systemic administration of an activation drug, to specifically activate D1-MSNs and stimulate the direct pathway.
In primate models with Parkinson’s disease, this circuit-specific approach led to significant improvements in motor symptoms. Bradykinesia was markedly reduced, tremors were completely eliminated, and motor skills were restored. Unlike L-Dopa treatment, which nonspecifically activates the dopamine system, this gene therapy precisely manipulates the D1-MSN-mediated direct pathway.
Furthermore, this gene therapy demonstrated a faster onset and longer duration of action compared to L-Dopa. The alleviation of symptoms persisted for over 24 hours following a single drug administration, compared to the typical six-hour window for L-Dopa. Importantly, motor complications such as dyskinesia, often seen with L-Dopa treatment, were absent after the gene therapy, even over an extended period exceeding eight months.
Beyond its potential to treat Parkinson’s disease, this circuit-manipulating gene therapy opens doors for the development of targeted therapeutic strategies for other brain disorders.
The study is published in the journal Cell.
BEIJING, China <unk> Maendeleo makubwa yamefanywa katika matibabu ya ugonjwa wa Parkinson kupitia maendeleo ya mkakati wa tiba ya jeni. Njia hii iliyoundwa na watafiti wa Kichina huelekeza kwa kuchagua mzunguko unaoathiriwa na ugonjwa wa Parkinson, kwa ufanisi kupunguza dalili za msingi za gari katika wanyama wa panya na wanyama wa primate wasio wanadamu. Ugonjwa wa Parkinson, hali ya kawaida ya neurodegenerative inayoathiri hasa wazee, ina sifa ya kupoteza neuroni za dopaminergic katika ubongo wa kati. Inasumbua watu zaidi ya milioni sita ulimwenguni pote. Kulingana na Michael J. Fox Foundation, dalili tatu muhimu za Parkinson ni pamoja na: - Stiffness (rigidity): misuli stiffness aligundua na daktari juu ya uchunguzi. - Uwepesi (bradykinesia): kupungua kwa harakati za hiari na za hiari; inaweza kujumuisha kutembea polepole, kutikisa mikono kidogo wakati wa kutembea, au kupungua kwa kung'aa au kujieleza kwa uso. - Kutetemeka kwa kupumzika: kutetemeka kwa rhythmic, bila kujitolea ambayo hutokea katika kidole, mkono au kiungo wakati ni kupumzika na kutoweka wakati wa harakati ya hiari. Ugonjwa wa ugonjwa wa DMSU unatokana na kutofautiana kwa aina mbili za neuroni za kati: neuroni za D1 za receptor ya dopamine (D1-MSN) na neuroni za D2 za D2-MSN. DMSN-1 huendeleza mwendo wa moja kwa moja, wakati DMSN-2 huwezesha mwendo wa moja kwa moja. Katika ugonjwa wa Parkinson, upungufu wa dopamine husababisha kupunguzwa kwa shughuli katika njia ya moja kwa moja na kuongezeka kwa shughuli katika njia ya moja kwa moja, ikisababisha dalili za gari kama bradykinesia (haraka ya harakati), ugumu, na kutetemeka. Matibabu ya msingi ya ugonjwa wa Parkinson, levodopa (L-Dopa), husaidia kurudisha kazi ya dopamine lakini inahusishwa na matatizo ya muda mrefu ya magari. Kwa hiyo, watafiti walitafuta mbinu sahihi zaidi na thabiti, kulingana na taarifa ya vyombo vya habari. Timu ya Chuo cha Sayansi cha China (CAS) ilichunguza uwezekano wa kulenga D1 - MSNs, neurons zinazohimiza harakati, kwa kuanzisha vipengele vya kudhibiti shughuli za neurons. Kwa mfano, kwa kutumia virusi vya retrograde adeno-associated (AAV) vinavyoitwa AAV8R12 na D1MN, G8P2 na G8P3 vinaweza kuathiri utendaji wa D1MN. Mkakati huu wa tiba ya jeni ulihusisha kuanzisha effector ya chemogenetic inayoitwa rM3Ds, ambayo ilifanana na utoaji wa mfumo wa dawa ya uanzishaji, kwa kuamsha D1 - MSN na kuchochea njia ya moja kwa moja. Katika mifano ya primate na ugonjwa wa Parkinson, mbinu hii ya mzunguko maalum ilisababisha maboresho makubwa katika dalili za gari. Bradykinesia ilipunguzwa sana, kutetemeka kuliondolewa kabisa, na ustadi wa utendaji wa mwili ukarudishwa. Tofauti na matibabu ya L-Dopa, ambayo huamsha mfumo wa dopamine bila maalum, tiba hii ya jeni inashughulikia kwa usahihi njia ya moja kwa moja ya D1-MSN. Kwa kuongezea, tiba hii ya jeni ilionyesha mwanzo wa haraka na muda mrefu wa hatua ikilinganishwa na L-Dopa. Kupunguzwa kwa dalili za ugonjwa huo kulidumu kwa zaidi ya masaa 24 baada ya matumizi ya dawa moja, ikilinganishwa na saa sita za kawaida kwa L-Dopa. Matatizo ya motor kama dyskinesia, ambayo mara nyingi huonekana na matibabu ya L-Dopa, hayakuwepo baada ya tiba ya jeni, hata kwa kipindi cha muda mrefu zaidi ya miezi minane. Zaidi ya uwezo wake wa kutibu ugonjwa wa Parkinson, tiba hii ya jeni ya kudhibiti mzunguko hufungua milango kwa ajili ya maendeleo ya mikakati ya matibabu ya lengo kwa matatizo mengine ya ubongo. Utafiti huo umechapishwa katika jarida la Cell.